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Type: Journal article
Title: Polymorphic hydroxylation of perhexiline in vitro
Author: Sorensen, L.
Sorensen, R.
Miners, J.
Somogyi, A.
Grgurinovich, N.
Birkett, D.
Citation: British Journal of Clinical Pharmacology, 2003; 55(6):635-638
Publisher: Blackwell Science Ltd
Issue Date: 2003
ISSN: 0306-5251
Statement of
L. B. Sørensen, R. N. Sørensen, J.O. Miners, A. A. Somogyi, N. Grgurinovich and D. J Birkett
Abstract: AIMS: The aims of this study were to examine the in vitro enzyme kinetics and CYP isoform selectivity of perhexiline monohydroxylation using human liver microsomes. METHODS: Conversion of rac-perhexiline to monohydroxyperhexiline by human liver microsomes was assessed using a high-performance liquid chromatography assay with precolumn derivatization to measure the formation rate of the product. Isoform selective inhibitors were used to define the CYP isoform profile of perhexiline monohydroxylation. RESULTS: The rate of perhexiline monohydroxylation with microsomes from 20 livers varied 50-fold. The activity in 18 phenotypic perhexiline extensive metabolizer (PEM) livers varied about five-fold. The apparent Km was 3.3 ± 1.5 µm, the Vmax was 9.1 ± 3.1 pmol min1 mg1 microsomal protein and the in vitro intrinsic clearance (Vmax/Km) was 2.9 ± 0.5 µl min1 mg1 microsomal protein in the extensive metabolizer livers. The corresponding values in the poor metabolizer livers were: apparent Km 124 ± 141 µm; Vmax 1.4 ± 0.6 pmol min1 mg1 microsomal protein; and intrinsic clearance 0.026 µl min1 mg1 microsomal protein. Quinidine almost completely inhibited perhexiline monohydroxylation activity, but inhibitors selective for other CYP isoforms had little effect. CONCLUSIONS: Perhexiline monohydroxylation is almost exclusively catalysed by CYP2D6 with activities being about 100-fold lower in CYP2D6 poor metabolizers than in extensive metabolizers. The in vitro data predict the in vivo saturable metabolism and pharmacogenetics of perhexiline.
Keywords: Microsomes, Liver; Humans; Quinidine; Perhexiline; Cytochrome P-450 CYP2D6; Enzyme Inhibitors; Hydroxylation; Genotype; Polymorphism, Genetic
Description: The definitive version is available at
RMID: 0020030555
DOI: 10.1046/j.1365-2125.2003.01805.x
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Appears in Collections:Pharmacology publications

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