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Chemical Disposition & Toxicokinetics

Technician placing blood tubes in laboratory centrifuge

Study Overview

Study: Chemical disposition (ADME), toxicokinetics
Species: Rats, mice

Description

Chemical disposition studies are performed to determine what happens to a substance in an organism after that organism is exposed. This process can be described by:

  • Absorption: the body absorbs the substance
  • Distribution: the substance is distributed into body blood and tissues
  • Metabolism: the body breaks down or metabolizes the substance
  • Excretion: the body excretes the substance

Based on these outcomes, chemical disposition studies are also called ADME studies. Toxicokinetics studies describe the rates at which a substance enters a biological system and what occurs to the substance once it is in the system.

Chemical Disposition Studies

Chemical disposition studies measure the absorption, distribution, metabolism, and excretion (ADME) of a chemical or substance. Studies are designed to determine the effect on each of these parameters of (1) species, (2) sex and age of animals, (3) dose level and frequency of dosing (e.g., single vs. repeated), and (4) route of exposure, and include an intravenous administration to determine the absorbed dose following dosing via the route of interest.

ADME studies use the radiolabeled chemical/substances (e.g., 14C or 2H), which enables easy detection of radiolabel equivalents in blood, tissues, and excreta. However, measuring radioactivity only monitors the total radiolabel and does not identify whether what is being measured is the parent chemical or one of its metabolites. Additional techniques such as chromatographic methods are used to differentiate between parent and metabolites.

Doses are typically set based on the reported LD50 values for a substance (e.g., 0.1, 0.01 and 0.001 of LD50). ADME studies are normally done very early in the sequence of studies used to fully characterize chemical toxicity, and their data are used to help set the dose and route of administration for subsequent toxicology studies.

Toxicokinetic Studies

Toxicokinetic (TK) studies follow the change in concentration of parent substances and/or metabolite(s) with time in blood/plasma or other tissues of interest. Like ADME studies, TK studies are designed to determine the effect of species, sex and age of animals, dose level and frequency of dosing (e.g., single vs. repeated), and route of exposure on TK parameters, and include an intravenous administration to determine the bioavailability following dosing via the route of interest.

TK studies are typically performed with unlabeled (no radioactivity) chemical/substance. Data from the ADME studies are generally used to determine the analytes to be monitored in TK studies using validated analytical methods such as gas chromatography- and liquid-chromatography-mass spectrometry. Doses are set based on the ADME and/or toxicology study doses. TK studies can be done early in the sequence of or in conjunction with studies used to fully characterize chemical toxicity. TK data are used to assist in the design and/or the interpretation of toxicology study data.

ADME and toxicokinetic studies are performed according to the NTP chemistry, ADME, and TK study specifications.

Glossary of Toxicokinetic Terms
Parameter Non-Compartmental Analysis Compartmental Analysis Definition
C_0min_pred C0 - Fitted plasma concentration at time zero (IV only).
Cmax Cmax_obs Cmax_predicted Observed or Predicted maximum plasma (or tissue) concentration.
Tmax Tmax_obs Tmax_predicted Time at which Cmax predicted or observed occurs.
Lambda_z Lambda_z - Non-compartmental analysis (NCA) terminal elimination rate constant, NCA ke or kelim.
Half-life HL_Lambda_z - Lambda z half-life, t½, the terminal elimination half-life based on non-compartmental analysis.
Alpha - Alpha Hybrid rate constant of the alpha phase.
Alpha_Half-life - Alpha_HL Half-life for the alpha phase.
Beta - Beta Hybrid rate constant of the beta phase.
Beta_Half-life - Beta_HL Half-life for the beta phase.
k01 - K01 Absorption rate constant, ka.
k01_Half-life - K01-HL Half-life for the absorption process to the central compartment.
k10 - K10 Elimination rate constant from the central compartment, also ke or kelim.
k10_Half-life - K10_HL Half-life for the elimination process from the central compartment.
k12 (k13, etc.) - K12 Distribution rate constant from the first to the second compartment, etc.
k21 (k31, etc.) - K21 Distribution rate constant from the second to the first compartment, etc.
Cl Cl_obs, Cl_F_obs - Clearance, includes total clearance.
Cl1 - CL Clearance from the central compartment, Clapp or apparent clearance for IV groups.
Cl2 - CLD2 Clearance from the secondary compartment.
Cl1_F Cl_F (gavage) CL_F Apparent clearance of the central compartment, also Cl_F for gavage groups in non-compartmental models.
Cl2_F - CLD2_F Apparent clearance from the secondary compartment.
V1 Vz_obs V1 Volume of distribution for the central compartment, includes Vd and V, volume of distribution; Vz, apparent volume of distribution for NCA; and Vapp, apparent volume of distribution for IV studies.
V2 - V2 Volume of distribution for the peripheral compartment.
Vss Vss_obs, Vss_pred Vss Volume of distribution at steady state.
V1_F Vz_F_obs V1_F Apparent volume of distribution for the central compartment, includes Vd_F, V_F (for oral groups), and Vc_F.
V2_F - V2_F Apparent volume of distribution for the peripheral compartment.
MRT MRTINF_obs, MRTINF_pred MRT Mean residence time.
AUC_0-T AUCall, AUClast - Area under the plasma concentration versus time curve, AUC, from time ti (initial) to tf (final).
AUCinf_pred AUCINF_pred AUCINF_pred Area under the plasma concentration versus time curve, AUC, extrapolated to time equals infinity.