Pharmacokinetic theory of cassette dosing in drug discovery screening

Cassette dosing is a procedure for higher-throughput screening in drug disc overy to rapidly assess pharmacokinetics of large numbers of candidate comp ounds. In this procedure, multiple compounds are administered simultaneousl y to a single animal. Blood samples are collected, and the plasma samples o btained are analyzed by means of an assay method such as liquid chromatogra phy coupled to tandem mass spectrometry that permits concurrent assay of ma ny compounds in a single sample. Consequently, the pharmacokinetics of mult iple compounds can be assessed rapidly with a small number of experimental animals and with shortened assay times. However, coadministration of multip le compounds may result in pharmacokinetic drug-drug interactions. This pap er describes a pharmacokinetic description for cassette dosing derived from pharmacokinetic theory. The most important finding from this theoretical t reatment is that the potential for drug-drug interactions leading to altere d clearances of coadministered drugs depends on both the relative K-M value s for the metabolic enzymes and the total number of drugs coadministered. H owever, the theory predicts that the potential for drug-drug interactions i s only a weak function of the dose size. Finally, it is also shown that inc luding a benchmark compound within the set of coadministered compounds cann ot ensure the detection of errors due to drug-drug interactions, Thus, neit her the absolute values of pharmacokinetic parameters nor the rank order ob tained from cassette dosing can be accepted without independent confirmatio n. These theoretical predictions are evaluated with data taken from the lit erature.