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https://hdl.handle.net/2440/14319
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dc.contributor.author | Sorensen, L. | - |
dc.contributor.author | Sorensen, R. | - |
dc.contributor.author | Miners, J. | - |
dc.contributor.author | Somogyi, A. | - |
dc.contributor.author | Grgurinovich, N. | - |
dc.contributor.author | Birkett, D. | - |
dc.date.issued | 2003 | - |
dc.identifier.citation | British Journal of Clinical Pharmacology, 2003; 55(6):635-638 | - |
dc.identifier.issn | 0306-5251 | - |
dc.identifier.issn | 1365-2125 | - |
dc.identifier.uri | http://hdl.handle.net/2440/14319 | - |
dc.description | The definitive version is available at www.blackwell-synergy.com | - |
dc.description.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. | - |
dc.description.statementofresponsibility | L. B. Sørensen, R. N. Sørensen, J.O. Miners, A. A. Somogyi, N. Grgurinovich and D. J Birkett | - |
dc.language.iso | en | - |
dc.publisher | Blackwell Science Ltd | - |
dc.source.uri | http://www.blackwell-synergy.com/doi/abs/10.1046/j.1365-2125.2003.01805.x | - |
dc.subject | Microsomes, Liver | - |
dc.subject | Humans | - |
dc.subject | Quinidine | - |
dc.subject | Perhexiline | - |
dc.subject | Cytochrome P-450 CYP2D6 | - |
dc.subject | Enzyme Inhibitors | - |
dc.subject | Hydroxylation | - |
dc.subject | Genotype | - |
dc.subject | Polymorphism, Genetic | - |
dc.title | Polymorphic hydroxylation of perhexiline in vitro | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1046/j.1365-2125.2003.01805.x | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Somogyi, A. [0000-0003-4779-0380] | - |
Appears in Collections: | Aurora harvest 7 Pharmacology publications |
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