The Influence of CYP2D6 Genotype on Trough Plasma Perhexiline and Cis-OH-perhexiline Concentrations Following a Standard Loading Regimen in Patients with Myocardial Ischaemia

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2006 Feb 21

PMID 16487226

Citations 3

Authors

Benjamin J Davies

Janet K Coller

Heather M James

Andrew A Somogyi

John D Horowitz

Benedetta C Sallustio

Affiliations

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Abstract

Aims: CYP2D6 protein expression is determined by the number of functional CYP2D6 alleles. It is also higher in individuals with at least one CYP2D6*2 allele. This study has investigated the effect of the number of functional CYP2D6 alleles and the influence of CYP2D6*2 alleles on plasma perhexiline concentrations in patients administered a standard loading regimen over 3 days.

Methods: Eighteen patients with myocardial ischaemia who were not taking any drugs known to inhibit CYP2D6 metabolism in vivo commenced treatment with 200 mg of perhexiline twice per day. On the fourth day, blood was drawn for genotyping and the measurement of trough plasma concentrations of perhexiline and its major metabolite, cis-OH-perhexiline.

Results: The only genotypic CYP2D6 poor metabolizer had a trough plasma perhexiline concentration of 2.70 mg l-1 and no detectable cis-OH-perhexiline. The mean+/-SD trough plasma perhexiline concentration in patients with one functional allele was significantly higher (0.63+/-0.31 mg l-1, n=8, P=0.05) than in patients with two functional alleles (0.37+/-0.17 mg l-1, n=9). Conversely, the mean metabolic ratio was significantly lower in patients with one functional allele (2.90+/-1.76, P<0.01) compared with patients with two functional alleles (6.52+/-3.26). Patients with at least one CYP2D6*2 allele had a lower plasma perhexiline concentration (0.20+/-0.09 mg l-1, n=5, P<0.001) and a higher metabolic ratio (7.86+/-2.51, P<0.01) than the non-poor metabolizer patients with no CYP2D6*2 alleles (0.62+/-0.23 mg l-1 and 3.55+/-2.54, respectively, n=12).

Conclusion: Patients with only one functional allele and not CYP2D6*2 have diminished CYP2D6 metabolic capacity for perhexiline.

Citing Articles

Study of the roles of cytochrome P450 (CYPs) in the metabolism and cytotoxicity of perhexiline.

Ren Z, Chen S, Qin X, Li F, Guo L Arch Toxicol. 2022; 96(12):3219-3231.

PMID: 36083301 PMC: 10395006. DOI: 10.1007/s00204-022-03369-0.

Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium.

Chong C, Drury N, Licari G, Frenneaux M, Horowitz J, Pagano D Eur J Clin Pharmacol. 2015; 71(12):1485-91.

PMID: 26376650 DOI: 10.1007/s00228-015-1934-8.

Steady-state pharmacokinetics of the enantiomers of perhexiline in CYP2D6 poor and extensive metabolizers administered Rac-perhexiline.

Davies B, Herbert M, Coller J, Somogyi A, Milne R, Sallustio B Br J Clin Pharmacol. 2007; 65(3):347-54.

PMID: 17875193 PMC: 2291239. DOI: 10.1111/j.1365-2125.2007.03015.x.

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