The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09-3566%20NTP-ITOX-R1.pdf). The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.
The Immunotoxicity of Clarithromycin
in Female B6C3F1 Mice
NTP Report Number IMM97007
Clarithromycin (CRTM) is a semi-synthetic macrolide antibiotic used in the treatment of disseminated mycobacterial infections which occur in late stage AIDS patients with histories of multiple opportunistic infections1. CRTM is also being used with increasing frequency to treat upper and lower respiratory tract infections, steroid-dependent asthma2, gastric H. pylori infections, and may also be used in combination therapy to treat M. leprae infections1. In addition to its' antimicrobial properties, clinical trials have reported that CRTM has both antiinflammatory and immunomodulatory properties, both of which have contributed to the increasing popularity of this antibiotic2.
Clarithromycin was nominated to the NTP for toxicological evaluation and was selected for immunotoxicity studies by the project officer. The purpose of these studies is to determine the potential effects of CRTM on the immune system.
The study reported here is an immunotoxicological study conducted in female B6C3F1 mice, treated daily for 28 days by oral gavage. The in-life phase of the study was conducted between September 30, 1997 and October 8, 1998. CRTM was prepared weekly as a solution in the vehicle 0.5% methyl cellulose.
The baseline toxicology studies are summarized in Table ES-1. In this study, in which CRTM was administered orally at 125, 250 and 500 mg/kg/day for 28 days, there were no effects on body weight or weight gain. There were no notable changes among the standard toxicological parameters that were assessed.
The immunological studies are summarized in Table ES-2. Minimal immunotoxicological effects were observed in mice treated with CRTM, and they were clearly not dose-dependent. There was a 14% increase in the antibody-forming cell response to sRBCs observed in the 250 mg/kg CRTM treatment group. However, this response was not considered to be biologically meaningful in that the response was not dose-dependent. A 27% increase in the number of spleen macrophages was observed in mice treated with 125 mg/kg CRTM; however, this increase was also not dose-dependent. In addition to its lack of effect on humoral immunity, CRTM did not affect either cell-mediated immunity nor innate immunity, as indicated by no significant immunotoxicological effect on the mixed leukocyte response, NK activity, and cytotoxic T lymphocyte activity, or change spleen NK cell, B cell, and T cell numbers.
In conclusion, CRTM treatment, ranging from 125 mg/kg to 500 mg/kg, produced no significant toxicological effects as indicated by weight change, pathology, and hematological parameters. Minimal immunotoxicological effects were observed in mice treated with CRTM, and they were clearly not dose-dependent. CRTM did not significantly affect total spleen cell o r leukocyte sub-population numbers, and no significant changes in humoral immunity, cellmediated immunity, or innate immunity were observed. Based on these results, 28 days of treatment with CRTM does not appear to be immunotoxic to the murine immune system within the tested dose range.
1 American Foundation for AIDS Research, Vol 8, No. 1, February 1996.
2 Frost, D.A., Leung, D.M., Matrin, R.J., Brown, E.E., Szefler, S.J., and Spahn, J.D. (1999). Inhibition of methylperdnisolone elimination in the presence of clarithromycin therapy. J. Allergy Clin. Immunol. 103:1031-5.
|Day 8||No Effect|
|Day 15||No Effect|
|Day 22||No Effect|
|Day 29||No Effect|
|Day 8-1||No Effect|
|Day 15-1||No Effect|
|Day 22-1||No Effect|
|Day 29-1||No Effect|
|Gross Pathology||No Effect|
|Leukocyte Diff||No Effect|
|Surface Markers (Absolute Values)|
|IgM Humoral Immune Response to Sheep Erythrocytes|
|IgM AFC/106 Cells||
|Mixed Leukocyte Response|
|NK Cell Activity|
Report Date: August 2000