Nonlinear Pharmacokinetics of Oral Quinidine and Verapamil in Healthy Subjects: A Clinical Microdosing Study
Kazuya Maeda, Junichi Takano, Yasumasa Ikeda, Tomoe Fujita, Y Oyama, Kazutaka Nozawa, Yoshito Kumagai, Yuichi Sugiyama
Clinical Pharmacology & Therapeutics June 29, 2011 DOI: 10.1038/clpt.2011.108 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | Healthy subjects |
| Interventions | Verapamil Quinidine |
| Topics | Microdosing |
| Keywords | Quinidine Verapamil Pharmacokinetics Clinical pharmacology |
| Citations | 50 |
| Key findings | The dose-normalized AUC of quinidine and verapamil increased 2.6- and 2.3-fold at therapeutic doses versus microdoses, indicating nonlinear pharmacokinetics likely due to saturation of MDR1 and/or CYP3A4 in the small intestine. |
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.
Comparable studies
Other observational and cohort studies on microdosing, most cited first.
Citations in the library
Cited by 12
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- Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development Clinical and Translational Science February 26, 2016
- Microdosing: A Critical Assessment of Human Data Journal of Pharmaceutical Sciences August 23, 2012
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