Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia.
OBJECTIVE
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.
Inglis
Sally C
SC
Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA 5011, Australia.
Herbert
Megan K
MK
Davies
Benjamin J L
BJ
Coller
Janet K
JK
James
Heather M
HM
Horowitz
John D
JD
Morris
Raymond G
RG
Milne
Robert W
RW
Somogyi
Andrew A
AA
Sallustio
Benedetta C
BC
D001682:Biological Availability; D002317:Cardiovascular Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008657:Metabolic Clearance Rate; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism*; D010480:Perhexiline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
D002317:Cardiovascular Agents; D019389:Cytochrome P-450 CYP2D6; C023470:perhexiline maleate; D010480:Perhexiline