Influence of the CYP2D6*10 Allele on the Metabolism of Mexiletine by Human Liver Microsomes

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2001 Jul 17

PMID 11453897

Citations 3

Authors

C SENDA

Y Yamaura

K Kobayashi

H Fujii

H Minami

Y Sasaki

T Igarashi

K Chiba

Affiliations

Soon will be listed here.

Abstract

Aims: To study the influence of CYP2D6*10 on the formation of p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM) using microsomes from human liver of known genotypes.

Methods: Microsomes from human livers of genotype CYP2D6*1/*1 (n = 5), *1/*10 (n = 6) and *10/*10 (n = 6) were used in this study. The formation of PHM and HMM was determined by high-performance liquid chromatography.

Results: The formation rates of PHM and HMM were decreased by more than 50% and 85% in CYP2D6*1/*10 and *10/*10 microsomes, respectively, compared with *1/*1 microsomes.

Conclusions: The metabolism of mexiletine to form PHM and HMM appears to be impaired to a significant extent in human liver microsomes from hetero- and homozygotes of CYP2D6*10.

Citing Articles

Functional and structural characterisation of common cytochrome P450 2D6 allelic variants-roles of Pro34 and Thr107 in catalysis and inhibition.

Dong A, Ahemad N, Pan Y, Palanisamy U, Yiap B, Ong C Naunyn Schmiedebergs Arch Pharmacol. 2019; 392(8):1015-1029.

PMID: 31025144 DOI: 10.1007/s00210-019-01651-0.

A Study on CYP2C19 and CYP2D6 Polymorphic Effects on Pharmacokinetics and Pharmacodynamics of Amitriptyline in Healthy Koreans.

Ryu S, Park S, Lee J, Kim Y, Na H, Lim H Clin Transl Sci. 2017; 10(2):93-101.

PMID: 28296334 PMC: 5355968. DOI: 10.1111/cts.12451.

Impact of CYP2D6*10 on mexiletine pharmacokinetics in healthy adult volunteers.

Otani M, Fukuda T, Naohara M, Maune H, Senda C, Yamamoto I Eur J Clin Pharmacol. 2003; 59(5-6):395-9.

PMID: 12937870 DOI: 10.1007/s00228-003-0656-5.

References

Kubota T, Yamaura Y, Ohkawa N, Hara H, Chiba K . Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol. 2000; 50(1):31-4. PMC: 2014971. DOI: 10.1046/j.1365-2125.2000.00209.x. View

Campbell N, Kelly J, Adgey A, Shanks R . The clinical pharmacology of mexiletine. Br J Clin Pharmacol. 1978; 6(2):103-8. PMC: 1429421. DOI: 10.1111/j.1365-2125.1978.tb00833.x. View

Turgeon J, Fiset C, Giguere R, Gilbert M, Moerike K, Rouleau J . Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man. J Pharmacol Exp Ther. 1991; 259(2):789-98. View

Broly F, Vandamme N, Libersa C, Lhermitte M . The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation. Br J Clin Pharmacol. 1991; 32(4):459-66. PMC: 1368606. DOI: 10.1111/j.1365-2125.1991.tb03931.x. View

Fukuda T, Yamamoto I, Nishida Y, Zhou Q, Ohno M, Takada K . Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers. Br J Clin Pharmacol. 1999; 47(4):450-3. PMC: 2014246. DOI: 10.1046/j.1365-2125.1999.00913.x. View