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

Inglis, S.C., Herbert, M.K., Davies, B.J.L., Coller, J.K., James, H.M., Horowitz, J.D., Morris, R.G., Milne, R.W., Somogyi, A.A. and Sallustio, B.C. (2007) Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia. Pharmacogenetics and Genomics, 17(5), pp. 305-312. (doi: 10.1097/FPC.0b013e32800ffba0)

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. 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. 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inglis, Dr Sally
• Authors: Inglis, S.C., Herbert, M.K., Davies, B.J.L., Coller, J.K., James, H.M., Horowitz, J.D., Morris, R.G., Milne, R.W., Somogyi, A.A., and Sallustio, B.C.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Pharmacogenetics and Genomics
• ISSN: 1744-6872