Nonlinear Pharmacokinetics of Oral Quinidine and Verapamil in Healthy Subjects: A Clinical Microdosing Study

Microdosing studies help identify early pharmacokinetic properties of drugs in humans, but nonlinearity between microdose and therapeutic dose due to saturation of metabolic enzymes and transporters is a concern. In healthy subjects, verapamil and quinidine, substrates of MDR1 and CYP3A4, showed dose-dependent pharmacokinetics. Dose-normalized AUC values increased 2.6-fold for quinidine and 2.3-fold for verapamil at therapeutic doses compared to microdoses, suggesting saturation of MDR1 and/or CYP3A4 in the small intestine causes nonlinearity.

Study at a glance

Abstract

Microdosing studies are effective in enabling the early identification of the pharmacokinetic properties of compounds administered to humans. However, the nonlinearity of the pharmacokinetics between microdose and therapeutic dose, attributable to the saturation of metabolic enzymes and transporters, is a major concern. Verapamil and quinidine are good substrates of both the multidrug resistance 1 transporter (MDR1) and the cytochrome P450 (CYP) 3A4 enzyme (CYP3A4). We investigated their dose-dependent pharmacokinetics in healthy subjects. Four different doses of verapamil or quinidine were administered orally to each subject, and the plasma concentrations of the parent drugs and their major metabolites were measured. The dose-normalized area under the plasma concentration-time curve (AUC) values of quinidine and verapamil increased in a dose-dependent manner and were 2.6- and 2.3-fold higher, respectively, at the therapeutic dose than at microdose. These results suggest that the nonlinear pharmacokinetics of these drugs is caused mainly by the saturation of MDR1 and/or CYP3A4 in the small intestine.