Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia

Inglis, SC; Herbert, MK; Davies, BJL; Coller, JK; James, HM; Horowitz, JD; Morris, RG; Milne, RW; Somogyi, AA; Sallustio, BC

Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia

Inglis, SC

Herbert, MK Davies, BJL Coller, JK James, HM Horowitz, JD Morris, RG Milne, RW Somogyi, AA Sallustio, BC

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Publication Type:: Journal Article
Citation:: Pharmacogenetics and Genomics, 2007, 17 (5), pp. 305 - 312
Issue Date:: 2007-05-01

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Field	Value	Language
dc.contributor.author	Inglis, SC https://orcid.org/0000-0002-1331-5912	en_US
dc.contributor.author	Herbert, MK	en_US
dc.contributor.author	Davies, BJL	en_US
dc.contributor.author	Coller, JK	en_US
dc.contributor.author	James, HM	en_US
dc.contributor.author	Horowitz, JD	en_US
dc.contributor.author	Morris, RG	en_US
dc.contributor.author	Milne, RW	en_US
dc.contributor.author	Somogyi, AA	en_US
dc.contributor.author	Sallustio, BC	en_US
dc.date.issued	2007-05-01	en_US
dc.identifier.citation	Pharmacogenetics and Genomics, 2007, 17 (5), pp. 305 - 312	en_US
dc.identifier.issn	1744-6872	en_US
dc.identifier.uri	http://hdl.handle.net/10453/16977
dc.description.abstract	AIMS: This study investigated the effects of increasing doses of rac-perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (-)-perhexiline. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. © 2007 Lippincott Williams & Wilkins, Inc.	en_US
dc.relation.ispartof	Pharmacogenetics and Genomics	en_US
dc.relation.isbasedon	10.1097/FPC.0b013e32800ffba0	en_US
dc.subject.classification	Pharmacology & Pharmacy	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Myocardial Ischemia	en_US
dc.subject.mesh	Perhexiline	en_US
dc.subject.mesh	Cytochrome P-450 CYP2D6	en_US
dc.subject.mesh	Cardiovascular Agents	en_US
dc.subject.mesh	Metabolic Clearance Rate	en_US
dc.subject.mesh	Sensitivity and Specificity	en_US
dc.subject.mesh	Retrospective Studies	en_US
dc.subject.mesh	Prospective Studies	en_US
dc.subject.mesh	Biological Availability	en_US
dc.subject.mesh	Genotype	en_US
dc.subject.mesh	Phenotype	en_US
dc.subject.mesh	Polymorphism, Genetic	en_US
dc.subject.mesh	Stereoisomerism	en_US
dc.title	Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	17	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	0604 Genetics	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/IMPACCT
utslib.copyright.status	closed_access
pubs.issue	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	17	en_US

Abstract:

AIMS: This study investigated the effects of increasing doses of rac-perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (-)-perhexiline. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. © 2007 Lippincott Williams & Wilkins, Inc.

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http://hdl.handle.net/10453/16977