Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide

Bae, Jung‐Woo; Oh, Kyung-Yul; Yoon, So-Jung; Shin, Hyo-Bin; Jung, Eui Hyun; Cho, Chang‐Keun; Lim, Chang Woo; Kang, Pureum; Choi, Chang‐Ik; Jang, Choon‐Gon; Lee, Seok‐Yong; Lee, Yun Jeong

doi:10.1007/s12272-020-01293-4

Cited by 28 publications

(9 citation statements)

References 31 publications

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“…Furthermore, also a previous study 20 did not show any time effects on the hearts in this model and a certain influence of the duration of perfusion cannot be totally excluded. Moreover, the concentrations of MCP in this study were 10‐100‐fold higher than plasma levels in healthy humans, whereas reduced kidney function 16 and CYP polymorphism 15 or CYP inhibitory comedications can significantly increase plasma concentrations of MCP.…”

Section: Discussionmentioning

confidence: 54%

“…After consecutive 5 minutes perfusion with a physiological potassium concentration, the hearts were perfused with 10 µM metoclopramide and the above‐mentioned protocol was repeated, as with 50 µM MCP and 100 µM MCP. These 10‐100‐fold supratherapeutic concentrations 14 were chosen in order to outline possible proarrhythmic actions by MCP and with respect to a possible MCP accumulation in CYP‐polymorphisms 15 and renal failure 16 …”

Section: Methodsmentioning

confidence: 99%

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Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model

Wolfes

Ellermann

Burde

et al. 2021

Basic Clin Pharma Tox

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Background Metoclopramide (MCP) is a dopamine D2‐receptor antagonist, mainly used to treat post‐operative or chemotherapy‐induced nausea. While it is very effective in the cure of gastric symptoms, MCP can cause severe neurologic side effects. Furthermore, there is growing evidence for severe arrhythmic side effects resulting from inhibitory effects on cardiac sodium and potassium channels. Methods and Results Thirteen hearts of New Zealand white rabbits were retrogradely perfused, and electrophysiology studies were performed to obtain action potential duration (APD90) and effective refractory period (ERP). After generating baseline data, the hearts were perfused with increasing concentrations of metoclopramide (MCP 10 µM, MCP 50 µM, MCP 100 µM) and the standardized protocol was repeated for each concentration. Perfusion with MCP resulted in a significant prolongation of APD90 and QT interval. In parallel, the incidence of ventricular tachycardias was significantly increased by high doses of MCP. Conclusion This is the first experimental study that investigated the effect of increasing doses of metoclopramide on a sensitive whole‐heart model of proarrhythmia. MCP led to a significant increase in action potential duration and QT interval; meanwhile, the number of ventricular tachycardias was significantly increased.

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Section: Discussionmentioning

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model

Wolfes

Ellermann

Burde

et al. 2021

Basic Clin Pharma Tox

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“…The highly polymorphic enzyme CYP2D6 is one of the most vital metabolic enzymes, having over 100 known alleles. It participates in approximately 25% of drug metabolism, significantly affecting the pharmacokinetics and efficacy of its substrate drugs, such as metoclopramide 35 . There are many genotypes of CYP2D6 , and their activity differences mainly include changes in exons and the insertion and deletion of single nucleotide polymorphisms located in upstream and intron gene regions (eg, CYP2D6 *41 is g.2989G>A in intron 6) 36 .…”

Section: Discussionmentioning

confidence: 99%

“…It participates in approximately 25% of drug metabolism, significantly affecting the pharmacokinetics and efficacy of its substrate drugs, such as metoclopramide. 35 There are many genotypes of CYP2D6, and their activity differences mainly include changes in exons and the insertion and deletion of single nucleotide polymorphisms located in upstream and intron gene regions (eg, CYP2D6 *41 is g.2989G>A in intron 6). 36 CYP2D6 *10 is the most common variant, with a high proportion found in East Asian populations.…”

Section: Effects Of Cyp2d6 Polymorphisms On the Pharmacokinetics Of D...mentioning

confidence: 99%

Effects of CYP2D6 10 and 41 Variants in Healthy Chinese Men on the Pharmacokinetics of Dapoxetine

Wang,

Gao,

et al. 2024

The Journal of Clinical Pharma

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Dapoxetine is a selective serotonin reuptake inhibitor (SSRI) used to treat premature ejaculation (PE), mainly metabolized by CYP2D6, CYP3A4 and flavin‐containing monooxygenase 1. The purpose of the study was to evaluate the effect of CYP2D6 polymorphism on the pharmacokinetics of dapoxetine in healthy Chinese men. Thirty‐nine subjects who received a single oral dose of 30 mg dapoxetine hydrochloride were classified based on their CYP2D6 genotype: *1/*1 (n = 9), *1/*41 (n = 1), *1/*10 (n = 12), *10/*41 (n = 3), *10/*10 (n = 14). The difference in pharmacokinetic parameters between different genotype groups was analyzed and then scored according to the activity score system. Compared to the wild‐type subjects of CYP2D6 *1/*1, the plasma peak concentration (Cmax) and area under the curve (AUCinf) of dapoxetine in *10/*10 and *10/*41 were notably increased (p ≤ 0.05). Significant differences were observed among the dapoxetine activity score groups in Cmax, AUC, V/F and CL/F (p ≤ 0.05). The AUCinf increased significantly (154% and 89.73%, p ≤ 0.05), and the Cmax increased significantly (73.45% and 42.67%, p ≤ 0.05) when comparing CYP2D6 *10/*41 subjects to *1/*1 and *1/*10 subjects. The obtained results indicated that CYP2D6 *10 and *41 polymorphisms have significant effects on the pharmacokinetic properties of dapoxetine.This article is protected by copyright. All rights reserved

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“…Bae et al [ 7 ] elucidated the association between pharmacokinetic properties of metoclopramide and the CYP2D6 polymorphism and documented a one-and-half-times elevation in the plasma concentration of metoclopramide and a 37% decrease in its clearance among wt/*10 carriers. By contrast, an Indonesia-based study hypothesized that the genetic polymorphism of CYP2D6 did not act on metoclopramide and ondansetron metabolisms [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Diltiazem efficacy and CYP2D6 gene polymorphism in patients with atrial fibrillation with rapid ventricular response

et al. 2023

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Background Diltiazem stands out as one of the front-line drugs administered in the emergency department to achieve acute rate control in patients suffering from atrial fibrillation with rapid Ventricular Response. One of the cytochrome enzymes involved in the metabolism of diltiazem is cytochrome P450 2D6 (CYP2D6). Interindividual differences can act on drug metabolism and thus drug efficacy due to the genetic polymorphism induced by the CYP2D6 enzyme. This study explores the association between the efficacy of diltiazem and the genetic polymorphism of CYP2D6 in patients with atrial fibrillation with rapid ventricular response. Results 87 out of 93 individuals with ventricular rate > 120 beats/min constituted the patient cohort. The patients were administered 0.25 mg/kg diltiazem intravenously. As a second dose, 0.35 mg/kg diltiazem was administered to patients who reportedly did not receive adequate drug efficacy. Heart rate control was considered to be achieved in patients whose heart rate fell below 110 beats/min and did not rise above 110 beats/min for 2 h. CYP2D6 *2, *3, *4 and *10 represent allele variants and *1 represents wild type (wt) allele. Achieving rate control after one or two doses of diltiazem in normal allele (wt/wt) carriers proved significantly higher than wt/*2, wt/*4 and wt/*10 heterozygous variant carriers. No significant difference was noted in wt/*3 heterozygous variant carriers. Conclusion The presence of *2, *4 and *10 alleles was observed to significantly compromise the drug efficacy. *3 allele was found to bear no relation to the effect of diltiazem on achieving rate control.

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Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide

Cited by 28 publications

References 31 publications

Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model

Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model

Effects of CYP2D6 10 and 41 Variants in Healthy Chinese Men on the Pharmacokinetics of Dapoxetine

Diltiazem efficacy and CYP2D6 gene polymorphism in patients with atrial fibrillation with rapid ventricular response

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Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide

Cited by 28 publications

References 31 publications

Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model

Proarrhythmic potential of metoclopramide in a sensitive whole‐heart model

Effects of CYP2D6 *10 and *41 Variants in Healthy Chinese Men on the Pharmacokinetics of Dapoxetine

Diltiazem efficacy and CYP2D6 gene polymorphism in patients with atrial fibrillation with rapid ventricular response

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Effects of CYP2D6 10 and 41 Variants in Healthy Chinese Men on the Pharmacokinetics of Dapoxetine