Relationship between plasma exposure of zolpidem and CYP2D6 genotype in healthy Korean subjects
- PDF / 888,819 Bytes
- 6 Pages / 595.276 x 790.866 pts Page_size
- 3 Downloads / 204 Views
Online ISSN 1976-3786 Print ISSN 0253-6269
RESEARCH ARTICLE
Relationship between plasma exposure of zolpidem and CYP2D6 genotype in healthy Korean subjects Eui Hyun Jung1 · Choong‑Min Lee1 · Ji‑Yeong Byeon1 · Hyo‑Bin Shin1 · Kyung‑Yul Oh1 · Chang‑Keun Cho1 · Chang Woo Lim1 · Choon‑Gon Jang1 · Seok‑Yong Lee1 · Yun Jeong Lee2
Received: 18 June 2020 / Accepted: 5 July 2020 © The Pharmaceutical Society of Korea 2020
Abstract Zolpidem, a widely prescribed hypnotic agent, is extensively metabolized by cytochrome P450 (CYP) 3A4, and CYP2C9, CYP1A2 and CYP2D6 are also involved in the metabolism of zolpidem. The aim of the study was to investigate the effects of CYP2D6 genotypes on the exposure of zolpidem. The healthy male volunteers were divided into three different genotype groups (CYP2D6*wt/*wt [*wt = *1 or *2], CYP2D6*wt/*10, and CYP2D6*10/*10). Each subject received a single oral dose of zolpidem 5 mg with or without a steady-state concentration of clarithromycin (a potent inhibitor of CYP3A4), and plasma concentrations of zolpidem were measured up to 12 h after zolpidem dosing by using liquid chromatography-tandem mass spectrometry method. When zolpidem was administered alone, the exposure of zolpidem (the total areas under the curve and the mean peak plasma concentrations) was not significantly different among three different genotype groups. Even with the steady-state concentration of clarithromycin, a potent CYP3A4 inhibitor, there were no significant differences in the exposure of zolpidem in relation to CYP2D6 genotypes. Keywords Zolpidem · CYP2D6 · Genotype · Polymorphisms · Pharmacokinetics Eui Hyun Jung and Choong-Min Lee have contributed equally to this study. * Seok‑Yong Lee [email protected] * Yun Jeong Lee [email protected] 1
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
2
College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
Introduction Inter-individual variation in the pharmacokinetics of numerous drugs are often due to genetic polymorphisms of drug metabolizing enzymes (DMEs), which can determine therapeutic response and as well as the risk for adverse reactions. Most of phase I and phase II DMEs are polymorphic and it was reported that the frequency of polymorphic DMEs depends on ethnicity and genetic polymorphisms of DMEs that are responsible for ethnic differences in drug disposition and response (Sim et al. 2013; Byeon et al. 2018c). Zolpidem, an imidazopyridine agent, is extensively used to treat insomnia in clinical practice (Hoehns and Perry 1993). Zolpidem is a γ-aminobutyric acid (GABA)A agonist and it binds with high affinity to benzodiazepine ω1 receptor (Langer and Arbilla 1988; Sanger and Depoortere 1998; Swainston Harrison and Keating 2005). The lower affinity for the other subtypes was expected to cause less rebound insomnia or tolerance than those seen with conventional benzodiazepines (Hesse et al. 2003). Zolpidem is rapidly absorbed with high bioavailability (70%) after oral administration (Langtry and Benfield 1990;
Data Loading...
