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.

Intravenous verapamil kinetics in rats: marked arteriovenous concentration difference and comparison with humans.

The pharmacokinetics of verapamil, a calcium channel blocker, were studied in male Sprague-Dawley rats following i.v. administration at a dose of 1 mg kg-1. Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed-phase high-performance liquid chromatography. Verapamil was distributed to the extravascular tissues very rapidly as indicated by the large Vdss (2.99 +/- 0.57 l kg-1) and Vd beta (5.08 +/- 0.54 l kg-1). The apparent terminal plasma T1/2, MRTiv, and CLp were 1.59 +/- 0.46, 1.26 +/- 0.12 h, and 40.4 +/- 9.73 ml min-1 kg-1, respectively. Marked arterial/venous differences were found with a considerable influence on the MRT and Vdss, and the terminal phase venous levels were higher than arterial levels by 103, 69, and 90%, respectively, for the three rats studied. The distribution of verapamil between plasma and erythrocytes occurred very rapidly and was identical in vitro and in vivo. The average blood to plasma and plasma to blood cell concentration ratios were 0.85 and 1.47, respectively. In contrast to propranolol, blood data rather than plasma data should be used to predict the hepatic extraction ratio of verapamil (0.87). The plasma protein binding of verapamil in humans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic parameters between rats and humans is presented and the potential shortcomings of using T1/2 or CLp and the advantage of using CLu (unbound plasma clearance) in interspecies scaling is also discussed.