Pharmacokinetic theory of cassette dosing in drug discovery screening.
Cassette dosing is a procedure for higher-throughput screening in drug discovery to rapidly assess pharmacokinetics of large numbers of candidate compounds. In this procedure, multiple compounds are administered simultaneously to a single animal. Blood samples are collected, and the plasma samples obtained are analyzed by means of an assay method such as liquid chromatography coupled to tandem mass spectrometry that permits concurrent assay of many compounds in a single sample. Consequently, the pharmacokinetics of multiple compounds can be assessed rapidly with a small number of experimental animals and with shortened assay times. However, coadministration of multiple compounds may result in pharmacokinetic drug-drug interactions. This paper describes a pharmacokinetic description for cassette dosing derived from pharmacokinetic theory. The most important finding from this theoretical treatment is that the potential for drug-drug interactions leading to altered clearances of coadministered drugs depends on both the relative K(M) values for the metabolic enzymes and the total number of drugs coadministered. However, the theory predicts that the potential for drug-drug interactions is only a weak function of the dose size. Finally, it is also shown that including a benchmark compound within the set of coadministered compounds cannot ensure the detection of errors due to drug-drug interactions. Thus, neither the absolute values of pharmacokinetic parameters nor the rank order obtained from cassette dosing can be accepted without independent confirmation. These theoretical predictions are evaluated with data taken from the literature.
White
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Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-1300, USA. ronald.white@spcorp.com
Manitpisitkul
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D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D010599:Pharmacokinetics; D011485:Protein Binding
D001798:Blood Proteins