National Toxicology Program

National Toxicology Program

CAS Registry Number: 33419-42-0 Toxicity Effects

http://ntp.niehs.nih.gov/go/24426

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • EPIPODOPHYLLOTOXIN, 4'-DEMETHYL-,4,6-O-ETHYLIDENE-BETA-D-GLYCOPYRANOSIDE (8CI)
  • 4-DEMETHYLEPIPODOPHYLLOTOXIN BETA-D-ETHYLIDENEGLUCOSIDE
  • Etoposide

Human Toxicity Excerpts

  • HUMAN EXPOSURE STUDIES: An Italian cohort consisted of 241 patients (132 boys and 109 girls) who were treated between 1977 and 1995 for newly diagnosed or relapsed Langerhans cell histiocytosis. The median length of follow-up was 5.8 years. The expected number of cases of leukemia was estimated from age- and sex-specific incidence rates derived from the Varese Cancer Registry in Italy. The standardized incidence ratio (SIR) of acute myeloid leukemia for the extended Italian cohort was 520 (95% CI, 168-1213). Eighty-two patients had received etoposide as a single agent or in combination with other drugs not known to be leukaemogenic, while 31 patients had received etoposide in combination with one or more agents with possible leukaemogenic activity (vincristine, prednisone, vinblastine, doxorubicin and cyclophosphamide); 128 patients were not treated with etoposide. The cumulative dose of etoposide ranged between 100 and 30 000 mg/sq m (median, 5200 mg/sq m); 70 children received more than 4000 mg/sq m. Five cases of acute promyelocytic leukemia were diagnosed, all in etoposide-treated patients (four girls, one boy; latency, 27-106 months). Four of the five patients had not been exposed to alkylating agents, intercalating agents or radiotherapy; the SIR for this group was 1600 (95% CI, 435-4096). The fifth case occurred in the group that had received both etoposide and alkylating agents, intercalating agents or radiotherapy (SIR, 776; 95% CI, 19-4325). All of the patients with acute promyelocytic leukemia had received a cumulative dose of etoposide exceeding 4000 mg/sq m, and the SIR for this group was 1782 (95% CI, 574-4159). No cases of acute promyelocytic leukemia were observed in patients who had not received etoposide.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 184 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: A study in Japan included 119 women who were treated for recurrent breast cancer between 1985 and 1994. Before recurrence, the patients had been treated with 5-fluorouracil, cyclophosphamide, doxorubicin, tamoxifen or radiation. All of the patients with recurrences were first treated with doxorubicin (or pirarubicin), vindesine and cyclophosphamide or cisplatin (or carboplatin). Twenty four patients received etoposide (orally at 50 or 100 mg per day for five to seven days at four-week intervals); the cumulative doses were < 2000 mg for seven patients, 2000-5000 mg for 10 and > 5000 mg for seven. The length of follow-up from the start of etoposide treatment ranged from 1 to 40 months. The cumulative risk for acute myeloid leukemia and myelodysplastic syndrome on the basis of three cases among the 119 patients was 9.1% (SE, 5.6%) 91-120 months after the operation. Two cases of acute myeloid leukemia and one of myelodysplastic syndrome developed in the subgroup of 24 patients who had received etoposide orally, and no cases occurred in the group that did not receive etoposide (p < 0.01; Fisher's exact test). The latency from start of etoposide treatment was 31 months, 25 months and seven months, and the cumulative doses of etoposide were 1750 mg, 11900 mg and 4550 mg, respectively.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 206 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: 119 patients with unresectable non-metastic lung cancer (histological type, other than small-cell) between 1981 and 1984 /were entered/ into a phase II trial of vindesine, etoposide (300 mg/sq m intravenously) and cisplatin; etoposide (300 mg/sq m intravenously) and cisplatin; or vindesine and cisplatin. The patients had had no prior chemotherapy. Twenty-four patients survived more than one year after initiation of therapy. Three of these had received vindesine and cisplatin, nine had received etoposide and cisplatin, and 12 had received vindesine, etoposide and cisplatin; 19 had received palliative radiotherapy (usually in the thorax). Four cases of acute myeloid leukemia occurred (two acute monoblastic leukemia, one acute myelomonocytic leukemia). The rate of acute myeloid leukemia was 0.30 per person-year (95% CI, 0.11-0.80), and the cumulative risk was 15% (95% CI, 2-45%) at two years. Two patients had received etoposide (7350 and 6240 mg/sq m) and cisplatin, and developed acute leukaemia 28 and 35 months after the start of therapy. The two others had received vindesine, etoposide (7950 and 4382 mg/sq m) and cisplatin, and developed acute myeloid leukaemia 19 and 13 months after the start of therapy, respectively. A comparison of the median cumulative dose of etoposide in the four patients with leukemia (6795 mg/sq m) and the 20 patients without leukemia (3025 mg/sq m) showed that those who eventually developed acute myeloid leukemia had received significantly more etoposide than those who did not (p < 0.01).[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 205 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: In a study in New York, USA, ... the risk for developing acute myeloid leukemia of 503 patients with advanced germ-cell tumours who had been treated with etoposide-containing therapy according to a cancer centre protocol between 1982 and 1990 /were investigated/. 340 patients with a minimum disease-free survival greater than one year were selected. Six patients with acute myeloid leukemia were identified; however, four of them had a mediastinal germ-cell tumor. One patient aged 31 with testicular cancer had received cisplatin, etoposide (cumulative dose, 2000 mg/sq m), vinblastine, bleomycin, dactinomycin and cyclophosphamide as induction plus salvage therapy. After 56 months, he developed acute myeloblastic leukemia. The second patient with testicular cancer, a man aged 35, had received induction therapy consisting of cisplatin, carboplatin and etoposide (cumulative dose, 1300 mg/sq m). After 26 months, he developed acute myeloblastic leukemia. Thus, one of the 310 patients (291 treated with bleomycin, carboplastin and cisplatin) who had received only one etoposide containing induction chemotherapy regimen subsequently developed acute myeloid leukemia, giving a definite incidence (an approximate actuarial risk) of less than 1.0% at five years.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 193 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: A cohort of 203 consecutive children aged 1 to 18 in Texas, USA, with early B-lineage acute lymphoblastic leukemia diagnosed in 1986 and 1991, who received induction treatment and achieved complete remission /were studied/. The induction and maintenance treatment consisted of prednisone, vincristine, daunorubicin, asparaginase, methotrexate, mercaptopurine, leucovorin, intravenous etoposide (300 mg/sq m) and cytarabine. The first 33 patients received teniposide instead of etoposide at half the dose. The planned cumulative dose of etoposide was 9900 mg/sq m. Only four patients received radiation therapy; none received alkylating agents. Ten children developed secondary acute myeloid leukemia, two of which were of the myelomonocytic type and two of the monoblastic type; one developed myelodysplastic syndrome (consistent with chronic myelomonocytic leukemia), and one had refractory anaemia with excess blasts in transformation. The interval between the diagnosis of acute lymphoblastic and acute myeloid leukemia ranged from 23 to 68 months. The median dose of etoposide administered was 7900 mg/sq m (range, 5100-9900 mg/sq m). One child with acute myeloid leukemia had received teniposide instead of etoposide. The risk for secondary acute myeloid leukemia at four years was 5.9% (SE, 3.2%), with risks for standard- and poor-risk patients of 6.3% (SE, 4.0%) and 4.7% (SE, 5.2%) respectively.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 202 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: The first results of a monitoring plan for secondary acute myeloid leukaemia in clinical trials of the Cancer Therapy Evaluation Program of the National Cancer Institute in the USA /was presented/. A total of 465 children (ages not given) with primary rhabdomyosarcoma (diagnosis around 1984) took part in this trial. The analysis was restricted to 207 children who had survived more than 36 weeks from entry into the protocol. They had received etoposide daily in combination with two courses of dactinomycin (cumulative dose of etoposide, 600 mg/sq m) or three courses of cisplatin (cumulative dose of etoposide, 900 mg/sq m), after they had been treated with induction regimens that included cyclophosphamide and doxorubicin. The mean duration of follow up was 3.7 years. Interim analyses of the risks for acute myeloid leukemia and myelodysplastic syndrome were carried out when four cases had been observed. Two of the four cases had received etoposide (600 mg/sq m) and dactinomycin, and two had received etoposide (900 mg/sq m) and cisplatin. The three cases of acute myeloid leukemia were of the myelomonocytic and monoblastic types and myelodysplastic syndrome progressing to acute myeloid leukemia; the other case was myelodysplastic syndrome. The patients in the two treatment groups in which these four cases occurred had been treated for induction of remission with similar doses of doxorubicin (480 mg/sq m), cyclophosphamide (24 000 mg/sq m) and cisplatin (360 mg/sq m). The latency ranged from 2.0 to 3.3 years. The calculated cumulative six year rate of development of acute myeloid leukemia or myelodysplastic syndrome was 3.2% (95% CI, 1.2-8.6%).[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 202 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Between 1984 and 1991, 1062 patients with rhabdomyosarcoma (age, 0 to 21 years) entered a trial in the USA. Of these, 223 patients received etoposide in combination with cyclophosphamide, vincristine, dactinomycin, doxorubicin and cisplatin, with a total dose of etoposide of 600-900 mg/sq m. All patients also received radiotherapy. The median follow-up time was 3.7 years. Four cases of acute myeloid leukemia, one of myelodysplastic syndrome and one of osteogenic sarcoma were reported. The median time from the initiation of primary treatment to the diagnosis of leukemia was 39 months. Three of four leukemia patients had received etoposide in combination with doxorubicin, cyclophosphamide (13000-21900 mg/sq m), cisplatin and other agents and radiotherapy during their treatment. The cumulative doses of etoposide were 643, 765, 911 and 3197 mg/sq m. Two cases were myelomonocytic and two were monoblastic leukemia. The incidence of acute myeloid leukemia among patients who had received etoposide in combination with doxorubicin, cyclophosphamide, cisplatin and other agents and radiotherapy during their treatment was 52 per 10 000 person–years. When cyclophosphamide alone or cyclophosphamide plus doxorubicin but no etoposide was part of the regimen, the incidence was 7.6 per 10 000 person-years. The relative risk for acute myeloid leukemia in a comparison of the etoposide-containing regimen and that without etoposide was thus 7.2 (95% CI, 0.8-65; p = 0.06). The patient who developed myelodysplastic syndrome after five years and seven months had received etoposide (840 mg/sq m) in combination with doxorubicin, cyclophosphamide (18500 mg/sq m), cisplatin and other agents and radiotherapy during his treatment.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 204 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: 38 patients, 2 to 17 years old, in Japan who were treated for non-Hodgkin lymphoma diagnosed between 1987 and 1991 with a protocol that included etoposide (cumulative dose, 5600 mg/sq m) /were reported/. Etoposide (200 mg/sq m) and behenoyl cytarabine were given twice weekly before and after a conventional four-week induction course of prednisolone, vincristine and L-asparaginase. Maintenance therapy consisted of 6-mercaptopurine and methotrexate, administered for 2.5 years, with five two-week pulses of etoposide (200 mg/sq m) and behenoyl cytarabine given every 10 weeks during the first year. All received periodic infusions of methotrexate and prophylactic cranial irradiation. The median follow-up was 19 months. Five of eight patients with hematological relapses developed secondary acute myeloid leukemia, with a cumulative risk at four years of 18.4% (Kaplan-Meier estimate). Two cases occurred in patients while they were being treated with etoposide. One had been treated for relapse of non-Hodgkin lymphoma with higher doses of etoposide, cyclophosphamide, doxorubicin and also ifosfamide, vincristine, pirarubicin and mitoxantrone. The five patients with acute myeloid leukemia had received a cumulative dose of etoposide of 4200-5600 mg/sq m; the latent period was 13-30 months. Four of the cases were acute monoblastic leukemia and the other was acute myeloblastic leukemia.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 205 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Between 1986 and 1990, 198 children under three years of age with primary brain tumors were included in /a/ USA /study/.Chemotherapy was started two to four weeks after surgery and consisted of vincristine, cyclophosphamide, cisplatinum and intravenous etoposide (6.5 mg/kg bw on days 3 and 4, every three months). Chemotherapy was planned for 24 months for children 0-23 months of age at diagnosis, and for 12 months for those 24-36 months of age. Irradiation therapy was started three to four weeks after the last cycle of chemotherapy. The median duration of follow-up for the 75 surviving children was 6.4 years. Five children developed a secondary malignancy. One developed a sarcoma, one a meningioma, and three developed hematological malignancies: two myelodysplastic syndromes with latencies of 7.7 and 4.8 years and an acute myeloid leukemia with a latency of 2.8 years. The child with acute myeloid leukemia had received a cumulative dose of etoposide of approximately 2400 mg/sq m. The actuarial risk for developing a second malignancy (solid or hematological) eight years after diagnosis was 11% (95% CI, 0-39).[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 204 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: ... The risk for acute myeloid leukemia after high cumulative dose of etoposide (> 2000 mg/sq m) and stem-cell transplantation in patients with advanced or relapsed germ-cell tumors. The records of 302 patients (median age, 29 years) with germ-cell tumors (241 testicular, 33 retroperitoneal and 28 mediastinal) who were treated with high-dose chemotherapy in clinical trials in Germany and France between 1986 and 1996 were reviewed. Patients had to have had a minimal follow-up of 12 months. Of the three German trials, the first included firstline therapy with one cycle of standard-dose cisplatin 20 mg/sq m, etoposide 100 mg/sq m and ifosfamide 1200 mg/sq m daily for five days followed by three to four cycles of of the same treatment escalated over seven doses: the highest consisted of 20 mg/sq m cisplatin, 300 mg/sq m etoposide and 2400 mg/sq m ifosfamide daily for five consecutive days every three weeks. In the second German trial, patients who relapsed after receiving cisplatin and etoposide-based chemotherapy received two cycles of a standard-dose cisplatin, etoposide and ifosfamide regimen followed by two cycles of 500 mg/sq m carboplatin, 400 mg/sq m etoposide and 2500 mg/sq m cyclophosphamide. In the third German trial, patients who relapsed after initial therapy with cisplatin and etoposide received two cycles of standard-dose cisplatin, etoposide and ifosfamide followed by carboplatin, 300-400 mg/sq m etoposide and ifosfamide. All the patients in France were treated with high-dose etoposide-containing chemotherapy including cisplatin, carboplatin and cyclophosphamide or ifosfamide, either as first-line consolidation therapy (patients with poor prognostic criteria) or as treatment for relapsed germ-cell tumour. All patients received either autologous bone marrow or autologous peripheral blood stem-cell support, and most patients also received granulocyte- or granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy. The median cumulative dose of etoposide was 5000 mg/sq m (range, 2400-4000 mg/sq m). Six patients developed a secondary hematological malignancy (four acute myeloid leukemias and two myelodysplastic syndromes). The two cases of myelodysplastic syndrome occurred in patients with a primary mediastinal germ-cell tumor and were excluded from the analysis. For the total group of 302 patients, the cumulative incidence of acute myeloid leukemia was 1.3% (95% CI, 0.4-3.4%) at a median follow-up time of 4.3 years. The standardized incidence ratio in comparison with data from the Saarland Cancer Registry in Germany for 1989-93 was 160 (95% CI, 44-411). The latency from start of etoposide treatment was 24–58 months. Two of the malignancies were acute monoblastic leukemia and two were acute myelomonocytic leukemia; three were found in patients with testicular cancer as the primary tumor.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 192 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: The risk for secondary neoplasms after therapy for germ-cell tumours in 1025 patients treated between 1970 and 1990 in Germany /was assessed/ . Patients followed-up for longer than 12 months were eligible (1018 patients; 394 had seminomatous germ-cell tumors). The median follow-up was 61 months, and the median age of the patients at diagnosis was 28.9 years. The chemotherapy regimens consisted mainly of cisplatin, bleomycin and either vinblastine or etoposide. A total of 293 patients received etoposide during their treatment: 221 patients received cumulative doses of -/= 2000 mg/sq m; 72 patients received > 2000 mg/sq m. The cumulative incidence of second tumours after etoposide-containing therapy was 1.0% (95% CI, 0.0-2.2), while that after chemotherapy without etoposide was 0.8% (95% CI, 0.0-2.5) (not significant). The standardized morbidity ratio of second malignancy for patients treated with etoposide was 2.3 (95% CI, 0.1-13 (not significant)) when compared with the cancer incidence rate in the male German population (based on the Saarland Cancer Registry). Among the 221 patients who received < or = 2000 mg/sq m etoposide, three developed a secondary tumor: one carcinoid tumor, one rhabdomyosarcoma and one lymphoblastic leukemia; the last patient had received four cycles of bleomycin, etoposide and cisplatin (cumulative dose of etoposide, 2000 mg/sq m), and the interval to second leukemia was 16 months. In patients who received > 2000 mg/sq m etoposide, no second malignancies occurred.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 190 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Four cases of acute myeloid leukemia and one of myelodysplastic syndrome in a cohort of 212 patients in Denmark with mostly testicular germ-cell tumours who had been treated with bleomycin, etoposide and cisplatin, none of whom had mediastinal germ-cell tumors /were described/. Thirty-five patients, treated between 1979 and 1983, received cisplatin, vinblastine and bleomycin and, at relapse, bleomycin (15 mg/sq m weekly), etoposide (120 mg/sq m for five days) and cisplatin (20 mg/sq m for five days). In the subgroup of 20 patients who had received a cumulative etoposide dose of > 2000 mg/sq m, two cases of acute myelomonocytic leukemia occurred. The latent periods after etoposide treatment were 25 and 54 months, respectively. For the 177 patients treated after 1983 to 1989 with first-line bleomycin, etoposide and cisplatin, the doses were adjusted according to risk category: 115 patients received standard doses (100 mg/sq m etopside for five days (cumulative dose, 2000 mg/sq m), 20 mg/sq m cisplatin for five days, 15 mg/sq m bleomycin weekly). No cases of acute myeloid leuk-aemia were diagnosed. In 62 patients who received high dose treatment consisting of etoposide (200 mg/sq m for five days; cumulative dose, 3000 mg/sq m), cisplatin (40 mg/sq m for five days) and bleomycin (15 mg/sq m weekly), two cases of acute myeloblastic leukemia (one in a patient with extragonal germ-cell tumor) and one case of myelodysplastic syndrome developed. The latencies after etoposide treatment were 15 and 29 months for acute myeloblastic leukemia and 68 months for the case of myelodysplastic syndrome. The expected number of de-novo cases of acute myeloid leukemia was estimated from the leukemia incidence reported in the Danish Cancer Registry for 1973-77. In comparison with the risk of the general population, the relative risk for overt leukaemia was 336 (95% CI, 92-861). The mean cumulative risk (Kaplan-Meier method) for leukaemic complications was 4.7% (SE, 2.3) 5.7 years after the start of etoposide-containing chemotherapy. No leukaemias or dysplastic syndromes were observed among the 130 patients who had received 2000 mg/sq m etoposide, whereas five cases were seen among the 82 patients who had received > 2000 mg/sq m (p = 0.004). The cumulative risk for leukaemia among the 82 patients receiving high-dose etoposide (> 2000 mg/sq m) was 11% (SE, 5.0) 5.7 years after the start of chemotherapy. Although five cases of leukemia and dysplastic syndrome were found in the 212 etoposide-treated patients, none was found in a previous cohort of 127 patients with germ-cell tumor treated with vinblastine and similar doses of cisplatin and bleomycin (p = 0.08).[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 186 (2000)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: The pharmacodynamics of total and unbound etoposide was studied in 28 adult patients with solid tumors who were receiving etoposide and cisplatin combination chemotherapy. Etoposide plasma concentrations were determined by use of an HPLC method, and etoposide plasma protein binding was determined by equilibrium dialysis. Patients with higher systemic exposure experienced greater hematologic toxicity. The sigmoid maximum effect model with unbound systemic exposure performed better (ie, lower residual sum of squares) than the model using total systemic exposure; in all patients (7043 versus 9755) and in the subset of patients who had not received previous chemotherapy (1986 versus 3664). The model estimates for unbound systemic exposure were more precisely estimated than for total systemic exposure (eg, coefficient of variation for the area under the concentration-time curve producing half of the maximal effect = 51% for total drug versus 21% for unbound drug). These findings indicate that the hematologic toxicity of etoposide is better correlated with systemic exposure to unbound drug than total drug, which may be of clinical importance because of the variable plasma protein binding of etoposide.[Stewart CF et al; Clin Pharmacol Ther 50 (4): 385-93 (1991)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/1914374?dopt=Abstract" target=new>PubMed Abstract</a>
  • CASE REPORTS: A woman was treated at 26 weeks of gestation with a combination of bleomycin, etoposide (165 mg/day) and cisplatin on three consecutive days for an unknown primary cancer. Six days later, she developed neutropenia and septicaemia and had a spontaneous vaginal delivery. The female infant developed profound leukopenia with neutropenia three days later (10 days after in-utero exposure), which had resolved by day 13. At 10 days of age, the infant started to lose her hair, which was growing again when she was discharged at 12 weeks. At follow-up at one year, she was essentially normal. A woman was treated for acute leukaemia at 25 and 30 weeks of gestation with cytarabine, daunorubicin and etoposide (400 mg/sq m per day for three days). Her infant, delivered by caesarean section at 32 weeks because of fetal distress, had leukopenia with profound neutropenia, which was confirmed to be due to bone-marrow suppression by measurement of circulating haemopoietic progenitor cells. This condition responded to transfusion of packed cells and subcutaneous injections of granulocyte colony-stimulating factor, and the infant was well at follow-up at one year. Three women treated for acute leukemia, ovarian cancer and non-Hodgkin lymphoma with multiple drug cycles including etoposide (100-125 mg/sq m per day) in the third trimester had normal, healthy infants.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 214 (2000)] **PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: After intravenous infusion of a single dose of 461 mg/sq m etoposide phosphate to dogs over 5 min, all animals vomited, and leukopenia and thrombocytopenia were seen at this and lower doses.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. v76 213 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Etoposide ... was examined for its oral, subcutaneous or intravenous acute toxicity using Slc:ICR mice, Crj:CD (Sprague-Dawley) rats and JW-NIBS rabbits of both sexes. The summarized results obtained are as follows: a mode of manifestation of toxic effects was classified into immediate type symptoms predominantly caused by the carrier and delayed type symptoms predominantly caused by etoposide regardless of animal species and routes of administration, excluding the case of intravenous dosing to rabbits. Referring to the delayed type toxic signs, depilation, diarrhea and suppression of body weight increase were observed for mice and rats regardless of administration routes, and diarrhea was noted in rabbits by oral route. Necropsy of three species of animals and histopathology on rabbits revealed thymic and splenic atrophy in mice and rats as well as thymic atrophy and inflammatory changes of intestine in rabbits dying by oral administration. The drug related cause of death for mice and rats seemed to be due to the cytocidal action of etoposide as an oncostatic drug, but the cause of death for rabbits by oral administration was considered to be somewhat different from that for mice and rats. LD50 values (mg/kg) showed toxicity in rabbits being rather potent as compared with that in mice or rats.[Takahashi N et al; J Toxicol Sci 11 (Suppl 1): 1-16 (1986)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Oral administration to rats and dogs at a dose of 0.5-5 mg/kg bw per day for five days a week for 26 weeks also resulted in myelosuppression as the major toxic effect in both species. No other effects were seen in the rats, while those in dogs included renal and hepatic impairment, electrocardiographic changes, decreased testis weight and disorders of spermatogenesis. These changes were largely reversible after four weeks without treatment.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 213 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Four-week studies of toxicity were conducted in rats treated intraperitoneally at 0.6-6.0 mg/kg bw per day and in monkeys treated intravenously at 0.4-3.6 mg/kg bw per day. At the highest doses, the main toxic effect was myelosuppression, with anaemia, leukopenia and thrombocytopenia, and some hepatotoxicity. Pathological changes were noted in the lung in rats, and mild enteritis was seen in dogs. After oral and intravenous administration at the same doses as in the previous studies, no additional toxicity was observed up to nine weeks.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 213 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Etoposide was tested in a neurofibromatosis type 1 (Nf1) transgenic knockout mouse model of myeloid leukaemia. Approximately 10% of heterozygous Nf1 mice (Nf1+/-) spontaneously develop myeloid leukaemia at around 15 months of age. Groups of 31 to 46 Nf1 wild-type (+/+) or Nf1 heterozygous (+/-) mice, 6 to 10 weeks of age [sex unspecified], were treated with 0 or 100 mg/kg bw etoposide weekly for six weeks by gastric intubation and were observed for up to 18 months. Histological examination was limited to smears of peripheral blood and, in some cases, bone marrow and spleen. The incidences of leukaemia were 2/31 in controls and 8/46 in Nf1+/+ and Nf1+/- mice compared with 0/26 in etoposide-treated Nf1+/+ and 8/32 in Nf1+/- mice (p = 0.20). In contrast, the alkylating agent, cyclophosphamide, induced myeloid leukaemias in 0/5 Nf1+/+ and 7/12 Nf1+/- treated mice.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 206 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Etoposide ... was administered orally to Crj:CD (Sprague-Dawley) rats of both sexes at dose levels of 1, 3, 10 and 30 mg/kg/day for six mo with the object of examining its chronic toxicity and the reversibility of toxic effects. The summarized results obtained are as follows: etoposide 30 mg/kg suppressed body weight increase and feed intake, and brought transient diarrhea, anemia and depilation. Some animals receiving this dose died showing systemic debility, emaciation and ataxia. Etoposide 3 mg/kg and higher predominantly decreased red blood cell count as well as white blood cell count accompanied with lowered lymphocyte fraction. Etoposide 30 mg/kg lowered total serum protein content and elevated A/G ratio in males, and lowered serum alkaline phosphatase activity in females. Etoposide 10 and 30 mg/kg predominantly induced thymic atrophy, testicular atrophy with suppression of spermatogenesis and tubular atrophy, a decrease in epididymal weight, and splenic erythropoiesis. Above described changes excluding the findings on testis and epididymis in etoposide 30 mg/kg group were shown to be generally reversible. Based on these results, the no-effect dose level of etoposide under the present experimental condition was estimated to be 1 mg/kg/day in rats of both sexes.[Takahashi N et al; J Toxicol Sci 11 (Suppl 1): 51-87 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3761400?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Etoposide has been shown to be teratogenic and embryocidal in mice and rats at doses of 1-3% of the recommended human dose based on body surface area. In rats, etoposide caused dose-related maternal toxicity, embryotoxicity, and teratogenicity with iv dosages of 0.4-3.6 mg/kg daily. Embryonic resorptions, decreased fetal weights, and fetal abnormalities including major skeletal anomalies, exencephaly, encephalocele, and anophthalmia, were observed; even at an iv dosage of 0.13 mg/kg daily, a substantial increase in retarded ossification occurred. In mice, intraperitoneal etoposide doses of 1-2 mg/kg caused dose-related embryotoxicity, cranial abnormalities, and major skeletal malformations.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 990] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Etoposide was administered intravenously to rats for 3 mo. Testicular alterations induced by etoposide at 0.5 and 1.5 mg/kg/day were thoroughly assessed with light and electron microscopy. Light microscopic analyses demonstrated disorganization and moderate depletion of germinal epithelium at 0.5 mg/kg/day, and complete germ cell depopulation at 1.5 mg/kg/day. Ultrastructural studies revealed degenerative changes in spermatogonia and early spermatocytes, appearance of large spermatids with multinuclei, and nuclear alterations and cytoplasmic vacuolation in Sertoli cells. Moreover, the basement membrane of the seminiferous tubule showed wavy lamellae and infolding to the seminiferous epithelium. Leydig cells manifested no significant ultrastructural changes. The small intestine and ovaries were not affected. The 2 month recovery period following cessation of treatment led to the recovery of these testicular alterations at the 0.5 mg/kg/day dose, but not at the 1.5 mg/kg/day dose. Judging from these results, etoposide induced damage primarily in spermatogenic cells, followed by Sertoli cells and the basement membrane in seminiferous tubules. Though reversible at intermediate doses, higher doses of etoposide might produce irreversible testicular lesions.[Kadota T et al; Toxicol Lett 45 (2-3): 185-94 (1989)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/2919399?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Etoposide ... was administered intravenously to male Crj:CD (Sprague-Dawley) rats for 61 days and to female rats of the same strain for 14 days prior to mating at dose levels of 0.05, 0.2 and 0.8 mg/kg/day. These animals were then mated under the consecutive administration of this drug and the females confirmed to be copulated were further dosed from day 0 through 7 of gestation. The summarized results obtained are as follows: body weight increases were suppressed at the dose level of etoposide 0.8 mg/kg in males and females. Etoposide 0.2 and 0.8 mg/kg decreased the thymic weight and 0.8 mg/kg decreased testicular and epididymal weight in males showing macroscopic atrophy of these organs, but these doses failed to affect the reproductive ability and so on in parent rats. As for fetuses, etoposide 0.8 mg/kg elevated the mortality, decreased the number of survivors and suppressed their growth. Furthermore, this dose raised the incidences of anophthalmia, microphthalmia, dilated lateral ventricles and unossified 5th and 6th sternums, as well as brought retarded ossification of sternums, cervical vertebrae, sacral and coccygeal vertebrae, metacarpus and thoracic vertebrae. Based on these results, the no-effect dose levels of etoposide under the present experimental condition were estimated to be 0.05 mg/kg/day against parent rats of both sexes and 0.2 mg/kg/day against their offspring.[Takahashi N et al; J Toxicol Sci 11 (Suppl 1): 263-79 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3761397?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Etoposide ... was administered orally to female Crj:CD (Sprague-Dawley) rats from day 17 of gestation through postpartum day 20 at dose levels of 1, 3 and 10 mg/kg/day. The summarized results obtained are as follows: etoposide 10 mg/kg induced thymic atrophy in dams. Etoposide failed to affect the parturition of dams. Etoposide 10 mg/kg lowered the viability of newborns (F1) on postpartum day 3 and increased the days required for descending of testes, but failed to affect the growth of genital organs, learning ability, motility, motor activity or emotional development. Etoposide 10 mg/kg brought a transient suppression of body weight increase in pregnant F1 rats, but failed to affect their reproductive ability and parturition. F2 newborns derived from F1 rats whose dams had never received etoposide during the prenatal and lactation periods showed no changes in observation items at birth. Long term rearing F1 rats derived from etoposide treated dams manifested no delayed toxicity including carcinogenicity. Based on these results, the no-effect dose level of etoposide under the present experimental condition was estimated to be 3 mg/kg/day against dams and their offspring.[Takahashi N et al; J Toxicol Sci 11 (Suppl 1): 241-61 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3761396?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Etoposide ... was administered orally to pregnant Crj:CD (Sprague-Dawley) rats from day 7 through 17 of gestation at dose levels of 1, 3 and 10 mg/kg/day. The summarized results obtained are as follows: etoposide 10 mg/kg suppressed the maternal body weight increase from day 12 through 20 of gestation. Etoposide 10 mg/kg brought the inhibition of fetal growth accompanied by the lowered values in body weight and body length. Furthermore, the elevated incidences of skeletal anomalies and unossified 5th and 6th sternums, as well as retarded ossification of thoracic vertebrae were also noted in this dose level. Etoposide 10 mg/kg induced anophthalmia, microphthalmia and dilated lateral ventricles in fetuses (F1), as well as unilateral anophthalmia in offspring (F1). Etoposide 10 mg/kg increased the days required for opening of eyelids and descending of testes in offspring (F1), but failed to affect their learning ability, motility, motor activity or emotional development. Etoposide 10 mg/kg suppressed the growth of genital organs in F1 rats of both sexes, but failed to affect their reproductive ability or gestation period. As for F2 newborns derived from F1 rats whose dams had never received etoposide 10 mg/kg during the period of fetal organogenesis, the number of implantations and survivors as well as birth indexes lowered due to changes in these items was restricted to a few litters. Based on these results, the no-effect dose level of etoposide under the present experimental condition was estimated to be 3 mg/kg/day against dams and their offspring.[Takahashi N et al; J Toxicol Sci 11 (Suppl 1): 195-225 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3761394?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Etoposide ... was administered orally to male Crj:CD (Sprague-Dawley) rats for 64 days and to female rats of the same strain for 15 days prior to mating at dose levels of 1, 3 and 10 mg/kg/day. These animals were then mated under the consecutive administration of this drug and the females confirmed to be copulated were further dosed from day 0 through 7 of gestation. The summarized results obtained are as follows: etoposide at 10 mg/kg suppressed the body weight increase in females from day 8 of pre-mating through day 20 of gestation, but did not affect the body weight in males. Etoposide at 10 mg/kg decreased the organ weights of testes, epididymides and thymus in males and induced atrophy of these organs macroscopically, but did not affect their reproductive performances. As for fetuses, etoposide at 10 mg/kg elevated the mortality and induced anophthalmia, microphthalmia and dilated lateral ventricles, as well as suppressed their growth and the ossification processes of sternums, sacral and coccygeal vertebrae, metacarpus, thoracic vertebrae and pubis. Based on these results, the no-effect dose level of etoposide under the present experimental condition was estimated to be 3 mg/kg/day against parent rats of both sexes and their offspring.[Takahashi N et al; J Toxicol Sci 11 (Suppl 1): 177-94 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3761393?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Five groups of eight pregnant Japanese white rabbits (Kbl:JW) were given etoposide at a dose of 0, 0.25, 0.5, 1.0 or 2.0 mg/kg bw per day intravenously on days 7, 8 and 9 of gestation. The fetuses were removed for visceral and skeletal examination on day 28 of gestation. The body-weight gain of dams was depressed and liver damage was observed at the highest dose, but fetal survival and weight were unaffected and no gross malformations were observed. A low incidence (4/64, p < 0.05) of fetuses with rib and vertebral abnormalities was noted. Histological examination of the fetal telencephalon showed no increase in cell death.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 217 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In a study of teratogenicity, groups of 11-21 JW-NIBS rabbits were given 0.3, 1, 3 or 10 mg/kg bw etoposide orally by gavage on days 6-18 of gestation. The highest dose caused marked depression of body-weight gain and food intake throughout gestation, and only two animals were alive at the end of the study. Deaths were observed at 3 mg/kg bw per day, and only 16/21 animals in this group were alive at termination. Doses up to and including 3 mg/kg bw had no adverse effect on embryo or fetal development, fetal weight, ossification or the incidence of malformations.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 217 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 23-24 pregnant Crj:CD Sprague-Dawley rats were given etoposide intravenously at a dose of 0.05, 0.2 or 0.8 mg/kg bw from day 17 of gestation until day 20 post-partum. Animals at the intermediate and high doses had reduced body-weight gain and thymic atrophy, but the duration of gestation and parturition was not affected. Treatment had no effect on pup survival, but their body-weight gain was transiently suppressed. Other aspects of postnatal, physical, functional and behavioural development were unaffected, except for a slight delay in vaginal opening by 1.4 days in the group at the high dose. The reproductive function of the F1 generation was normal, and the growth and development of the F2 generation were normal.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 216 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 20-22 male Crj:CD Sprague-Dawley rats were treated with etoposide at a dose of 0.05, 0.2 or 0.8 mg/kg bw intravenously for 61 days and females for 14 days before mating, and treatment was continued during mating and, for females, until day 7 of gestation. The high dose suppressed body-weight gain in animals of each sex. In males at the high dose, the weights of the testis and epididymides were reduced, and the organs appeared atrophic macroscopically; however, reproductive function was not significantly affected. The weight of the thymus was reduced at the intermediate and high doses. Females at the high dose had smaller litters and more resorptions than controls. Fetal body weight was significantly reduced, and the number of malformed fetuses was increased when compared with controls. The malformations observed included cerebral ventricular dilatation, anophthalmia and microphthalmia.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 216 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Etoposide has been reported to cause degeneration of rat spermatogonia and early spermatocytes, the appearance of large multinucleated spermatids and nuclear and cytoplasmic changes in Sertoli cells. The stage-specific changes produced by etoposide were studied by following effects on DNA synthesis as measured by incorporation of 3(H)thymidine. Groups of three Sprague-Dawley rats, two to three months of age, were injected intraperitoneally with 5 or 10 mg/kg bw etoposide and killed 1, 3 or 18 days later. Premitotic DNA synthesis was inhibited by about 40-70% in spermatogonial stages II-V at both doses, when compared with controls. The effects on premeiotic DNA synthesis were less marked, with a maximum inhibition of about 40%. Markedly increased incorporation of thymidine was also observed at stage VII, at which no DNA synthesis normally occurs. The effects of etoposide were most marked after one and three days, but some effects were still present 18 days after treatment.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. v76 217 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Day-10 rat embryos [strain not specified] cultured for 24 hr in vitro were exposed for the first 3 hr to etoposide at concentrations of 1.0-10 umol/L. A dose-related increase in the incidence of malformations was observed at doses of 2.0 and 5.0 umol/L, and at the latter concentration 100% of the embryos were malformed. The dose of 10 mol/L was lethal to all embryos. The malformations observed consisted mainly of hypoplasia of the prosencephalon, microphthalmia and oedema of the rhombencephalon. ...[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. v76 216 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 4-10 pregnant Swiss albino mice were given a single dose of etoposide at 1.0, 1.5 or 2.0 mg/kg bw intraperitoneally on day 6, 7 or 8 of gestation (vaginal plug, day 0), and the fetuses were removed and examined on day 17. No effect on maternal body-weight gain was seen in any group. In animals injected on day 6, no embryotoxicity was seen with 1.0 or 1.5 mg/kg bw, but 2.0 mg/kg bw increased the frequencies of intrauterine death, fetal malformations and reduced fetal body weight. Injection on day 7 caused dose-related embryolethality, fetal malformations and reduced fetal weight. Injection on day 8 caused no embryolethality and no effect on fetal body weight, but the frequency of fetal malformations was increased at doses of 1.0 and 2.0 mg/kg bw. The commonest malformations observed at the highest dose were hydrocephalus (12.2%) and open eyelids (16.7%) after injection on day 6, exencephaly and encephalocoele at frequencies of 13% and 10% on days 7 and 8 and axial skeletal defects at frequencies of 28% and 7.7% on days 7 and 8, respectively.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 215 (2000)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 22-24 pregnant Crj:CD Sprague-Dawley rats were given etoposide at a dose of 1, 3 or 10 mg/kg bw orally by gavage from day 17 of gestation until day 20 post-partum. The high dose produced thymic atrophy in the dams but did not affect the duration of gestation or parturition. The mortality rate of pups was slightly increased during the first three days after birth, and their body-weight gain was transiently suppressed. Other aspects of postnatal physical, functional and behavioural development were unaffected. The reproductive function of the F1 generation was normal, and the growth and development of the F2 generation were normal. Long-term observation of the F1 animals showed no delayed toxicity or carcinogenesis.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 216 (2000)] **PEER REVIEWED**
  • GENOTOXICITY: Etoposide gave mainly negative responses in a range of assays in prokaryotes and lower eukaryotes. Thus, in most studies, it did not cause significant increases in reverse mutation frequency as measured in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100, Escherichia coli WP2 uvrA, E. coli K12 (forward and reverse mutation) and in other E. coli assays in the presence or absence of exogenous metabolic activation. Etoposide caused a slight (about twofold) increase in the frequency of revertant colonies in S. typhimurium TA102 and a clearly positive response in strain TA1978. It caused differential toxicity in Bacillus subtilis H17 rec+ and M45 rec-. Toxicity but not mutagenicity occurred at a dose of about 800 ug/plate, which is higher than those studied in mammalian cells. In Saccharomyces cerevisiae strain D5, etoposide did not induce either mitochondrial 'petite' mutations or mitotic recombination. It did not induce forward or reverse mutations in Neurospora crassa.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 225 (2000)] **PEER REVIEWED**
  • GENOTOXICITY: Most of the translocations with which etoposide is associated in treated patients involve chromosome band 11q23, but this and other DNA topisomerase II inhibitors have also been associated with leukemias with t(8;21), t(3;21), inv(16), t(15;17) or t(9;22) translocations. These are also the common translocations in de-novo cases of leukaemia; however, while translocations of chromosome band 11q23 are present in most cases of acute lymphoblastic leukemia in infants and cases of monoblastic leukemia in infants and young children, they are found in only about 5% of acute leukemias in adults. More recently, chromosome band 11p15 was recognized as a site of recurrent translocations in leukemias that follow etoposide-containing therapy.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 219 (2000)] **PEER REVIEWED**
  • GENOTOXICITY: In adult Sprague-Dawley rats injected intraperitoneally with a single dose of 5 or 10 mg/kg bw etoposide, it was a powerful inducer of micronuclei in early spermatids, whereas the major cytotoxic action is on the early spermatogonial stages. Thus, the cytotoxicity is separate from genotoxicity[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. v76 217 (2000)] **PEER REVIEWED**
  • GENOTOXICITY: Etoposide has been shown to induce chromosomal aberrations in embryonic murine cells and in human hematopoietic cell lines in vitro; gene mutations in Chinese hamster ovary cells; and DNA damage via strand breakage and DNA-protein crosslinks in mouse leukemia cells. The drug also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 989-90] **PEER REVIEWED**
  • GENOTOXICITY: In the micronucleus test, etoposide and teniposide induced significantly micronucleated polychromatic erythrocytes of the bone marrow cells in mice; 3.3-4.3% at the doses of 0.75-6 mg/kg and 4.0-6.1% at 0.5-4 mg/kg, respectively.[Nakanomyo H et al; J Toxicol Sci 11 (Suppl 1): 301-10 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3761399?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: ... Etoposide treatment of phytohaemagglutinin-stimulated human lymphocytes in culture is associated with an excess frequency of reciprocal translocations in addition to other abnormalities, which include dicentrics and, less often, unbalanced or complex rearrangements, deletions and inversions. Chromosomes 1, 11 and 17 are frequent targets of these abnormalities.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 218 (2000)] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Etoposide is known to inhibit the activity of topoisomerase II, and to possess radiosensitizing effects. Pretreatment of mice with etoposide one day before whole body irradiation had a protective effect against radiation induced bone marrow death. The LD50/30 of mice given radiation alone was 8.26 Gy while that of mice given etoposide one day before whole body irradiation was 10.35 Gy. The number of endogenous colony forming units surviving in whole body irradiated mice was significantly increased by pretreatment with etoposide.[Yamada S et al; Jpn J Cancer Res 81 (2): 112-4 (1990)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/2110126?dopt=Abstract" target=new>PubMed Abstract</a>

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Mouse IV 118 mg/kg bw[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 213 (2000)] **PEER REVIEWED**
  • LD50 Rat IV 68 mg/kg bw[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 213 (2000)] **PEER REVIEWED**
  • LD50 Rabbit IV > 80 mg/kg bw[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 213 (2000)] **PEER REVIEWED**
  • LD50 Mouse ip 108 mg/kg bw[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 213 (2000)] **PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Excretion of etoposide in breast milk was demonstrated in a woman with acute promyelocytic leukemia receiving daily doses of 80 mg/sq m (route not stated). Peak concentrations of 0.6 to 0.8 ug/mL were measured immediately after dosing but had decreased to undetectable levels by 24 hr.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 214 (2000)] **PEER REVIEWED**
  • Thirty minutes after intravenous administration of etoposide to rats, the highest concentrations were found in the liver, kidneys and small intestine. By 24 hr after the dose, the tissue concentrations were negligible.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 211 (2000)] **PEER REVIEWED**
  • After intravenous infusion (5 min) of etoposide phosphate to beagle dogs at doses of 57-461 mg/sq m, a dose-proportional increase was seen in the maximal plasma concentration and AUC for etoposide. The total plasma clearance rate (342-435 mL/min per sq m) and the distribution volume (22-27 L/sq m) were not dose-dependent. The peak plasma concentration occurred at the end of the infusion of etoposide phosphate, indicating rapid conversion of the pro-drug to etoposide.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 211 (2000)] **PEER REVIEWED**
  • Less than 4% of a dose was recovered in the bile after 48 hr in patients with biliary drainage tubes. The fecal recovery of radiolabel after intravenous administration of 3(H)etoposide (130-290 mg/sq m) was variable, representing 0-16% of dose, but the collections were known to be incomplete because of fecal retention and other difficulties associated with the poor general condition of many of the patients). In a study reported as an abstract in four patients with small-cell lung cancer given 14(C)-glucopyranoside etoposide, 56% of the radiolabel was recovered in urine and 44% in feces over five days, for a total recovery of 100 +/- 6%.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 210 (2000)] **PEER REVIEWED**
  • Little etoposide penetrates into other fluid spaces, almost certainly because of its extensive protein binding. The concentrations of etoposide in cerebrospinal fluid were only 1 to 2% of the plasma concentration after high doses, and none was detectable after a standard dose of etoposide. Etoposide was detectable in brain tumors after standard doses, at concentrations higher than in the cerebrospinal fluid immediately after administration of a high dose (400 to 800 mg/sq m by infusion), but the concentrations in tumours were generally lower in primary or metastasized intracerebral than in extracerebral tumours. The concentration in saliva after a high dose was only 1.5% of the concurrent plasma concentration at several intervals. After administration of a high dose, the peak concentrations in ascites and pleural fluid were considerably lower than the peak plasma concentration, but at later times (> 10 hr) the concentrations were higher than in plasma, suggesting slow clearance from these fluid compartments.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 208 (2000)] **PEER REVIEWED**
  • In one study, the bioavailability of a 100-mg dose was 76%, while that of a 400 mg dose was 48% (p < 0.01). This effect might be related to a concentration-dependent reduction in the solubility of etoposide in the stomach and small intestine. The bioavailability of etoposide varies widely among and within patients.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 207 (2000)] **PEER REVIEWED**
  • In vitro, etoposide is approximately 94% bound to serum proteins at a concentration of 10 ug/ml.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 991] **PEER REVIEWED**
  • Following iv infusion of etoposide, plasma concentrations of the drug have generally been reported to decline in a biphasic manner; however, some data indicate that the drug may exhibit triphasic elimination with a prolonged terminal phase. In adults with normal renal and hepatic function, the half-life of etoposide averages 0.6-2 hours ... in the initial phase and 5.3-10.8 hours ... in the terminal phase. In one adult with impaired hepatic function, the terminal elimination half-life was reportedly 78 hours. In children with normal renal and hepatic function, the half-life of etoposide averages 0.6-1.4 hours in the initial phase and 3-5.8 hours in the terminal phase.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 991] **PEER REVIEWED**
  • Metabolism and excretion of etoposide appear to be similar following oral or iv administration of the drug. Etoposide and its metabolites are excreted principally in urine; fecal excretion of the drug is variable. Following iv infusion of etoposide in patients with normal renal and hepatic function, approximately 40-60% of a dose is excreted in urine as unchanged drug and metabolites within 48-72 hours and from less than 2 to 16% is excreted in feces within 72 hours; about 20-30% of the dose is excreted in urine unchanged within 24 hours and 30-45% within 48 yours. The principal urinary metabolite is the hydroxy acid of the drug. Following oral administration in patients with normal renal and hepatic function, about 5-25% of the dose is excreted in urine within 24-48 hours.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 991] **PEER REVIEWED**
  • Total plasma clearance of etoposide reported averages 19-28 ml/minute per sq m in adults and 18-39 ml/minute per sq m in children with normal renal and hepatic function; renal clearance of the drug is approximately 30-40% of the total plasma clearance. ... Individuals with decreased renal function may have impaired elimination. Limited evidence suggests that total plasma clearance and elimination of etoposide may be reduced in patients with impaired hepatic function.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 991] **PEER REVIEWED**
  • Peak plasma concentration and areas under the plasma concn-time curve following iv administration of etoposide exhibit marked interindividual variation, but possibly less intraindividual variation than after oral administration. Over the dose range of 100-600 mg/sg m, peak plasma concentration and areas under the plasma concn-time curve increase linearly with dose. Following iv infusion of an 80 mg/sq m dose of etoposide over 1 hour in adults with normal renal and hepatic function, peak plasma drug concentrations occurred at the end of the infusion and averaged 14.9 ug/ml. ... Following 500 mg/hour iv infusion of 400, 500, 600 mg/sq m in adults with normal renal function in one study, peak plasma etoposide concentrations of 26-53, 27-73, and 42-114 ug/ml, respectively, were attained. When etoposide was administered as a 72 hour continuous iv infusion in a dosage of 100 mg/sq m daily in several patients with normal renal and hepatic function, plasma drug concentrations of about 2-5 ug/ml were attained 2-3 hours after beginning the infusion and were maintained until the end of the infusion. In a limited number of children 3 months to 16 years of age with normal renal and hepatic function who were given iv infusions of 200-300 mg/sq m over 0.5-2.25 hours, peak serum etoposide concentrations ranged from 17-88 ug/ml.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 990] **PEER REVIEWED**
  • Following iv administration of etoposide in mice and rats, highest concentrations of the drug are attained in the small intestine, kidneys, and liver, with lower concentrations in the lungs, stomach, pancreas, spleen, heart, and skin.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 990] **PEER REVIEWED**
  • Following iv administration in humans, etoposide undergoes rapid distribution. The apparent steady-state volume of distribution of the drug averages 20-28% of body weight or 18-29 L or 7-17 L/sq m in adults and 5-10 L/sq m in children. The major metabolite of etoposide appears to be distributed into a volume approximately equal to total body water. Following iv administration, etoposide is distributed minimally into pleural fluid and has been detected in the saliva, liver, spleen, kidney, myometrium, healthy brain tissue, and brain tumor tissue. Limited data suggest that distribution of the drug into bile is minimal. It is not known if etoposide is distributed into milk. The drug apparently crosses the placenta in animals.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 990] **PEER REVIEWED**
  • Etoposide and its metabolites apparently do not readily penetrate the CNS. ... CSF etoposide concentrations generally range from undetectable to less than 5% of concurrent plasma concentrations during the initial 24 hours after IV administration of the drug, even after administration of very high doses. ... Etoposide distributes into brain tumor tissue more readily than into healthy brain tissue. Concentrations of the drug are higher in healthy lung tissue than in lung metastases but those achieved in primary myometrial tumors are similar to those achieved in healthy myometrial tissues.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 991] **PEER REVIEWED**
  • Etoposide is variably absorbed following oral administration. The extent of absorption of etoposide is not affected by food. ... Lipophilic capsules containing etoposide were found to be erratically absorbed and produced dose limiting adverse GI effects. An oral solution of the drug (known as the "drink ampul") was about 50-90% absorbed but was unpalatable. ... Following oral administration of the commercially available capsules, peak plasma etoposide concentrations are generally attained within 1-1.5 hours and peak plasma concentrations and area under the plasma concentration-time curve exhibit marked intraindividual and interindividual variation. However, peak plasma concentrations and area under the plasma concentration-time curve for a given oral dose consistently fall in the same range as those following an iv dose one half as large. ... Following oral administration of 160 or 200 mg/sq m as the commercially available capsules, peak plasma etoposide concentrations of 9 ug/mg .. and 9.6 ug/ml ... respectively, were attained. There is no evidence that the drug undergoes first-pass metabolism.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 990] **PEER REVIEWED**
  • The pharmacokinetics of high dose etoposide (total dose, 2100 mg/sq m divided into three doses given as 30 min infusions on 3 consecutive days) were studied in ten patients receiving high dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2 X 60 mg/kg cyclophosphamide and either 6 X 1,000 mg/sq m cytosine arabinoside, 300 mg/sq m carmustine or 1,200 mg/sq m carboplatin. Plasma etoposide concentrations were determined by 252Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma etoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were: half-life beta, 256 + or - 38 min; mean residence time, 346 + or - 47 min; area under the curve 4,972 + or - 629 ug/min/ml (normalized to a dose of 100 mg/sq m); volume of distribution at steady state, 6.6 + or - 1.2 l/sq m; and clearance, 20.4 + or - 2.4 ml/min/m. A comparison of these values with standard dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70-700 mg/sq m). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 hr after the last etoposide infusion) ranged between 0.57 and 2.39 ug/ml, all patients exhibited undelayed hematopoietic reconstitution.[Kohl P et al; Cancer Chemother Pharmacol 29 (4): 316-20 (1992)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/1537079?dopt=Abstract" target=new>PubMed Abstract</a>
  • Etoposide pharmacokinetics were investigated in 3 groups of cancer patients: a control group of 18 patients with renal and hepatic function tests in the normal range; a group of 8 patients with renal insufficiency; and a group of 15 patients with abnormal hepatic function. In the control group plasma clearance, volume of distribution, and elimination half-life of etoposide were, respectively, 22.8 + or - 1.0 (standard error) ml/min/sq m, 11.4 + or - 0.8 liters/sq m, and 5.6 + or - 0.4 hr. In patients with renal insufficiency plasma clearance was 12.8 + or - 1.1 ml/min/sq m, volume of distribution was 20.8 + or - 4.9 liters/sq m and elimination half-life was 19.2 + or - 4.7 hr. A statistically significant correlation (p = 0.0000001) was found between etoposide plasma clearance and creatinine clearance. In 12 of 15 patients with abnormal liver tests plasma clearance, volume of distribution, and elimination half-life were, respectively, 27.9 + or - 2.7 ml/min/sq m, 12.4 + or - 1.5 liters/sq m, and 5.4 + or - 0.6 hr and are thus similar to those of the control group. In the other 3 cases with abnormal liver function etoposide plasma levels were very low. In these cases etoposide elimination half-life values were similar (5.1, 4.4, and 5.1 hr) whereas plasma clearance values (320, 87, and 96 ml/min/sq m) and volume of distribution values (142, 33, and 42 liters/sq m) were much larger than in controls. These results suggest that etoposide doses should be reduced in patients with renal function impairment but not necessarily in patients with liver impairment. The high volume of distribution and plasma clearance values found in a subset of patients with liver impairment require further elucidation.[D'Incalci M et al; Cancer Res 46 (May): 2566-71 (1986)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/3697995?dopt=Abstract" target=new>PubMed Abstract</a>
  • The pharmacokinetics of intravenously administered etoposide in children is similar to that in adults, with a total plasma clearance of 20 to 40 mL/min per sq m in children and 15 to 35 mL/min per sq m in adults, a distribution volume of 5 to 10 L/sq m in children and 7 to 17 L/sq m in adults and an elimination half-life of 3 to 7 hr in children and 4 to 8 hr in adults. In most studies, a bi-exponential elimination is described, with a distribution half-life of about 1 hr.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 207 (2000)] **PEER REVIEWED**

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Metabolism/Metabolites

  • The proposed hydroxy acid metabolite of etoposide, formed by opening of the lactone ring, has been detected in human urine, but only at low concentrations, accounting for 0.2-2.2% of the administered dose.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 210 (2000)] **PEER REVIEWED**
  • The major urinary metabolite of etoposide in humans is reported to be the glucuronide conjugate. Although urinary glucuronide and/or sulfate conjugates were reported to account for 5-22% of an intravenous dose of etoposide, other studies suggest that the glucuronide predominates. Etoposide glucuronide in the urine of treated patients accounted for 8-17% of a dose of 0.5-3.5 g/sq m etoposide and 29% of a dose of 100-800 mg/sq m etoposide, with no other metabolites other than etoposide glucuronide detected in the latter study. In patients with renal or liver impairment given somewhat lower doses of 70-150 mg/sq m, 3-17% of the dose was excreted in the urine within 72 hr as etoposide glucuronide.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 209 (2000)] **PEER REVIEWED**
  • Etoposide appears to be metabolized principally at the D ring to produce the resulting hydroxy acid (probably the trans-hydroxy acid); this metabolite appears to be pharmacologically inactive. The picrolactone isomer of etoposide has been detected in two concentrations in the plasma and urine of some patients but not in others. The aglycone of etoposide and/or its conjugates have not been detected to date in patients receiving the drug. In vitro, the picrolactone isomer and aglycone of etoposide have minimal cytotoxic activity.[McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 991] **PEER REVIEWED**
  • Generally, few or no etoposide metabolites have been detected in plasma. Etoposide is administered as the trans-lactone, but cis-etoposide can also be detected in human urine. This might be a storage phenomenon, since isomerization sometimes occurs during freezing of plasma samples under slightly basic conditions. The cis isomer accounts for < 1% of the dose. The catechol metabolite has also been reported in patients receiving 600 mg/sq m etoposide, with an AUC of around 2.5% that of etoposide. In patients given 90 mg/sq m etoposide, the catechol metabolite represented 1.4-7.1% of the urinary etoposide and < 2% of the administered dose.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 208 (2000)] **PEER REVIEWED**
  • In rat liver homogenates, liver microsomes and in rats in vivo, etoposide was extensively metabolized to only one major metabolite, which was not formally identified. In perfused isolated rat liver incubated with etoposide, the total recovery in bile was 60-85%, with roughly equal amounts of etoposide and two glucuronide metabolites, confirmed as glucuronide species by liquid chromatography and mass spectrometry. After intravenous injection of 3(H)etoposide to rabbits, the total urinary excretion of radiolabel was 30% after five days, with very little thereafter. A single glucuronide metabolite was identified in rabbit urine, which was present in larger amounts than etoposide. No hydroxy acid was identified in either species.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V76 211 (2000)] **PEER REVIEWED**

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TSCA Test Submissions

  • None found

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 11/28/2012.

The NTP is administratively located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

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