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|Title:||Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose|
|Citation:||British Journal of Clinical Pharmacology, 2002; 54(2):107-114|
|Publisher:||Blackwell Science Ltd|
|Abstract:||AIMS:1) To develop an estimate of oral clearance (CL(Px)/F) for the antianginal agent perhexiline based on the ratio of cis-OH-perhexiline metabolite/parent perhexiline plasma concentrations at steady-state (C(OHPx,ss)/C(Px,ss)). 2) To determine whether the ratio measured in the first fortnight of treatment (C(i)(OHPx)/C(i)(Px)) may be used to guide patient dosing with perhexiline, a drug with a narrow therapeutic index, long half-life and saturable metabolism via CYP2D6. METHODS:Two retrospective studies were conducted reviewing patient records and data obtained from routine monitoring of plasma perhexiline and cis-OH-perhexiline concentrations. RESULTS:Study 1 (n=70). At steady-state, the frequency distributions of CL(Px)/F and C(OHPx,ss)/C(Px,ss) were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by CL(Px)/F< or =50 ml min(-1) or C(OHPx,ss)/C(Px,ss)< or =0.3. A group of patients with CL(Px)/F> or =950 ml min(-1) may have been ultra-rapid metabolizers. In this group, the high CL(Px)/F values suggest extensive first-pass metabolism and poor bioavailability. In patients with therapeutic plasma perhexiline concentrations (0.15-0.60 mg l(-1)), the variability in dose appeared directly proportional to CL(Px)/F (r2=0.741, P<0.0001). Study 2 (n=23). Using C(i)(OHPx)/C(i)(Px) patients were tentatively identified as poor, extensive and ultra-rapid metabolizers, with CL(Px)/F of 23-72, 134-868 and 947-1462 ml min(-1), respectively, requiring doses of 10-25, 100-250 and 300-500 mg day(-1), respectively. CONCLUSIONS:The cis-OH-perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.|
|Keywords:||Humans; Angina Pectoris; Perhexiline; Cytochrome P-450 CYP2D6; Cardiovascular Agents; Metabolic Clearance Rate; Chromatography, High Pressure Liquid; Sensitivity and Specificity; Retrospective Studies; Biological Availability; Phenotype|
|Appears in Collections:||Pharmacology publications|
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