Abstract
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 KM 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.
Footnotes
-
↵2 An important drug-metabolizing enzyme, CYP3A4, has been shown recently to have non-Michaelis-Menten kinetics (Houston and Kenworthy, 2000; Wang et al., 2000). A different enzyme rate equation applies to CYP3A4, but the general derivation being followed here would still be valid.
-
↵3 We can rigorously use the plasma concentration of the drug as a surrogate for the true intracellular concentration of drug seen by the enzyme by assuming rapid equilibration of plasma and hepatic concentrations and by expressing K values in terms of the corresponding plasma concentrations.
-
↵4 In general, compounds will not conveniently be at concentrations equal to their K values, and concentrations will not be equal to one another unless the volumes of distribution are equal. However, choosing a special case for ease of calculation does not alter the conclusions, since C is an explicit term for each compound in the equations.
-
↵5 A fourth paper, shown in Table 1 (Ward et al., 2001), was not included in this statement because the screening method that was used combined cassette dosing with a pharmacokinetic approximation so that results falling outside the right box (29%) cannot be clearly ascribed to the cassette dosing.
- Abbreviations used are::
- F, oral bioavailability
- AUC, area under the plasma concentration versus time curve
- CL
- plasma clearance
- ED
- enzyme-drug complex
- Received June 6, 2000.
- Accepted March 7, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
