Drug metabolism studies toxicological species

The two most common drug metabolism studies are mass balance and tissue distribution. Mass balance studies are usually conducted in both the rodent and the nonrodent species used for toxicology evaluations, whereas tissue distri-... 

The two most common drug metabolism studies are mass balance and tissue distribution. Mass balance studies are usually conducted in both the rodent and the nonrodent species used for toxicology evaluations, whereas tissue distribution is performed only in the rodent. For mass balance, a radio-labeled compound is administered to the test species and urine, feces, and, if necessary, expired air are collected at intervals and counted for total radioactivity. Commonly used intervals are 0-4, 4-8, 8-12, 12-24, and then daily, up to 168 hours or until more than 95% of the administered dose has been excreted. Depending on the pharmacokinetic profile of the candidate, other collection intervals can be selected to give a better picture of the excretion profile. For tissue distribution, a radiolabeled compound is administered to the test species, and after predefined times, usually 2, 4, 8, 24, and 48 hours, the test species... 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

Successful completion of the above experiments will characterize methods for use in evaluating a lead candidate in animal models. If a candidate is selected for further development, the method will need to be validated (3,4) for each matrix and for each species before being used to support definitive toxicology, drug metabolism, and pharmacokinetic studies. 

Experts in drug metabolism carry out time-course studies with radioactive samples. They give a variety of doses and, at intervals, measure plasma radioactivity rather than therapeutic effect. Sensitive instruments aUow for quantitative measurements for example, of the time and concentration at which radioactivity reaches a maximum. To lay a basis for seiecting the animal species used for long-term toxicology studies, these pilot probes of duration may employ several mammalian species. Different species metabolize a single drug dissimilarly, so a suitable animal species handles it as the human one does. 

Metabolism studies are required in the laboratory animal species used to determine the toxicological NOEL, as well as each food-producing animal species. ADIs are based on total residues of drug plus all metabolites, whereas MRLs comprise a single, quantifiable marker residue, most commonly the parent compound but in some instances a single metabolite or a mixture of compounds. To establish the MRL for each tissue, food consumption estimates are made on the basis of an assumed standard meal (the so-called food basket), as discussed further in Section 2.5.2.2. 

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