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https://hdl.handle.net/2440/42005
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dc.contributor.author | Inglis, S. | - |
dc.contributor.author | Herbert, M. | - |
dc.contributor.author | Davies, B. | - |
dc.contributor.author | Coller, J. | - |
dc.contributor.author | James, H. | - |
dc.contributor.author | Horowitz, J. | - |
dc.contributor.author | Morris, R. | - |
dc.contributor.author | Milne, R. | - |
dc.contributor.author | Somogyi, A. | - |
dc.contributor.author | Sallustio, B. | - |
dc.date.issued | 2007 | - |
dc.identifier.citation | Pharmacogenetics and Genomics, 2007; 17(5):305-312 | - |
dc.identifier.issn | 1744-6872 | - |
dc.identifier.issn | 1744-6880 | - |
dc.identifier.uri | http://hdl.handle.net/2440/42005 | - |
dc.description.abstract | <h4>Aims</h4>This study investigated the effects of increasing doses of rac-perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (-)-perhexiline.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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. | - |
dc.description.statementofresponsibility | Sally C. Inglis; Megan K. Herbert; Benjamin J.L. Davies; Janet K. Coller; Heather M. James; John D. Horowitz; Raymond G. Morris; Robert W. Milne; Andrew A. Somogyi; Benedetta C. Sallustio | - |
dc.language.iso | en | - |
dc.publisher | Lippincott Williams & Wilkins | - |
dc.source.uri | http://dx.doi.org/10.1097/fpc.0b013e32800ffba0 | - |
dc.subject | Humans | - |
dc.subject | Myocardial Ischemia | - |
dc.subject | Perhexiline | - |
dc.subject | Cytochrome P-450 CYP2D6 | - |
dc.subject | Cardiovascular Agents | - |
dc.subject | Metabolic Clearance Rate | - |
dc.subject | Sensitivity and Specificity | - |
dc.subject | Retrospective Studies | - |
dc.subject | Prospective Studies | - |
dc.subject | Biological Availability | - |
dc.subject | Genotype | - |
dc.subject | Phenotype | - |
dc.subject | Polymorphism, Genetic | - |
dc.subject | Stereoisomerism | - |
dc.title | Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1097/FPC.0b013e32800ffba0 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Coller, J. [0000-0002-8273-5048] | - |
dc.identifier.orcid | Horowitz, J. [0000-0001-6883-0703] | - |
dc.identifier.orcid | Somogyi, A. [0000-0003-4779-0380] | - |
dc.identifier.orcid | Sallustio, B. [0000-0002-0186-3073] | - |
Appears in Collections: | Aurora harvest Pharmacology publications |
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