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https://hdl.handle.net/2440/14323
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Type: | Journal article |
Title: | Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose |
Author: | Sallustio, B. Westley, I. Morris, R. |
Citation: | British Journal of Clinical Pharmacology, 2002; 54(2):107-114 |
Publisher: | Blackwell Science Ltd |
Issue Date: | 2002 |
ISSN: | 0306-5251 1365-2125 |
Abstract: | <h4>Aims</h4>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.<h4>Methods</h4>Two retrospective studies were conducted reviewing patient records and data obtained from routine monitoring of plasma perhexiline and cis-OH-perhexiline concentrations.<h4>Results</h4>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.<h4>Conclusions</h4>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 |
DOI: | 10.1046/j.1365-2125.2002.01618.x |
Published version: | http://dx.doi.org/10.1046/j.1365-2125.2002.01618.x |
Appears in Collections: | Aurora harvest 7 Pharmacology publications |
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