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Type: Journal article
Title: Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia
Author: Inglis, S.
Herbert, M.
Davies, B.
Coller, J.
James, H.
Horowitz, J.
Morris, R.
Milne, R.
Somogyi, A.
Sallustio, B.
Citation: Pharmacogenetics and Genomics, 2007; 17(5):305-312
Publisher: Lippincott Williams & Wilkins
Issue Date: 2007
ISSN: 1744-6872
Statement of
Sally C. Inglis; Megan K. Herbert; Benjamin J.L. Davies; Janet K. Coller; Heather M. James; John D. Horowitz; Raymond G. Morris; Robert W. Milne; Andrew A. Somogyi; Benedetta C. Sallustio
Abstract: <h4>Aims</h4>This study investigated the effects of increasing doses of rac-perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (-)-perhexiline.<h4>Methods</h4>In a prospective study, steady-state plasma concentrations of (+) and (-)-perhexiline were quantified in 10 CYP2D6 genotyped patients following dosing with 100 mg/day rac-perhexiline maleate, and following a subsequent dosage increase to 150 or 200 mg/day. In a retrospective study, steady-state plasma concentrations of (+) and (-)-perhexiline were obtained from 111 CYP2D6 phenotyped patients receiving rac-perhexiline maleate.<h4>Results</h4>In the prospective study, comprising one poor and nine extensive/intermediate metabolizers, the apparent oral clearance (CL/F) of both enantiomers increased with the number of functional CYP2D6 genes. In the nine extensive/intermediate metabolizers receiving the 100 mg/day dose, the median CL/F of (+)-perhexiline was lower than that of (-)-perhexiline (352.5 versus 440.6 l/day, P<0.01). Following the dosage increase, the median CL/F of both enantiomers decreased by 45.4 and 41.4%, respectively. In the retrospective study, the median (+)-/(-)-perhexiline plasma concentration ratio was lower (P<0.0001) in phenotypic extensive/intermediate (1.41) versus poor metabolizers (2.29). Median CL/F of (+) and (-)-perhexiline was 10.6 and 24.2 l/day (P<0.05), respectively, in poor metabolizers, and 184.1 and 272.0 l/day (P<0.001), respectively, in extensive/intermediate metabolizers.<h4>Conclusions</h4>Perhexiline's pharmacokinetics exhibit significant enantioselectivity in CYP2D6 extensive/intermediate and poor metabolizers, with both enantiomers displaying polymorphic and saturable metabolism via CYP2D6. Clinical use of rac-perhexiline may be improved by developing specific enantiomer target plasma concentration ranges.
Keywords: Humans
Myocardial Ischemia
Cytochrome P-450 CYP2D6
Cardiovascular Agents
Metabolic Clearance Rate
Sensitivity and Specificity
Retrospective Studies
Prospective Studies
Biological Availability
Polymorphism, Genetic
DOI: 10.1097/FPC.0b013e32800ffba0
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