Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide
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Online ISSN 1976-3786 Print ISSN 0253-6269
RESEARCH ARTICLE
Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide Jung‑Woo Bae1,2 · Kyung‑Yul Oh1 · So‑Jung Yoon1 · Hyo‑Bin Shin1 · Eui Hyun Jung1 · Chang‑Keun Cho1 · Chang Woo Lim1 · Pureum Kang1 · Chang‑Ik Choi3 · Choon‑Gon Jang1 · Seok‑Yong Lee1 · Yun Jeong Lee4
Received: 14 November 2020 / Accepted: 19 November 2020 / Published online: 27 November 2020 © The Pharmaceutical Society of Korea 2020
Abstract Metoclopramide inhibits the central and peripheral D2 receptors and is frequently prescribed in adults and children as an antiemetic or a prokinetic drug to control symptoms of upper gastrointestinal motor disorders. Metoclopramide is predominantly metabolized via N-dealkylation and it is primarily mediated by CYP2D6 which is highly polymorphic. Thus, the effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide were evaluated in this study. All volunteers were genotyped for CYP2D6 and divided into four different genotype groups (CYP2D6*wt/*wt [*wt = *1 or *2], CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10). Each subject received a single oral dose of metoclopramide 10 mg. Plasma concentrations of metoclopramide were measured by using HPLC-UV. Compared to CYP2D6*wt/*wt, AUCinf of CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10 significantly increased by 1.5-, 2.3-, and 2.5-fold, respectively. Cmax also increased significantly in comparison to CYP2D6*wt/*wt across all genotype groups, with 1.5-, Jung-Woo Bae and Kyung-Yul Oh 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, Keimyung University, Daegu 42601, Republic of Korea
3
College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
4
College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
1.7-, and 1.7-fold increases seen in CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10 groups, respectively. The CL/F of metoclopramide decreased in CYP2D6 genotype groups with decreased function alleles, as decreases of 37%, 56% and 61% were observed in CYP2D6*wt/10, *10/10, and *5/*10 genotype groups in comparison to the CYP2D6*wt/*wt group. In conclusion, the genetic polymorphisms of CYP2D6 significantly affected metoclopramide pharmacokinetics. Keywords Metoclopramide · CYP2D6 · Genotype · Genetic polymorphism · Pharmacokinetics
Introduction Metoclopramide is an antagonist of dopamine D 2 and 5-HT3 receptors and an agonist of 5-HT4 receptors (Tonini et al. 2004). It is frequently prescribed in adults and children as an antiemetic or a prokinetic drug to control the symptoms of upper gastrointestinal motor disorders, such as those seen in gastroesophageal reflux disease (GERD) (Rao and Camilleri 2010). It also can be used to treat hyperemesis gravidarum and post-chemotherapy or post-surgery nausea and vomiting (De Oliveira et al. 2012; McParlin et al. 2016; Masi
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