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.