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- Title
Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose.
- Authors
Sallustio, Benedetta C.; Westley, Ian S.; Morris, Raymond G.
- Abstract
Aims 1) To develop an estimate of oral clearance ( &formmu0;/F ) for the antianginal agent perhexiline based on the ratio of cis -OH-perhexiline metabolite/parent perhexiline plasma concentrations at steady-state &formmu1;. 2) To determine whether the ratio measured in the first fortnight of treatment &formmu2; 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 &formmu3;/F and &formmu4;/&formmu5; were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by &formmu6;/F ≤50 ml min-1 or &formmu7;/&formmu8;≤0.3. A group of patients with &formmu9;/F ≥950 ml min-1 may have been ultra-rapid metabolizers. In this group, the high &formmu10;/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 &formmu11;/F (r 2 =0.741, P <0.0001). Study 2 (n=23) . Using &formmu12;/&formmu13; patients were tentatively identified as poor, extensive and ultra-rapid metabolizers, with &formmu14;/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.
- Subjects
PERHEXILINE; PHARMACOKINETICS
- Publication
British Journal of Clinical Pharmacology, 2002, Vol 54, Issue 2, p107
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1046/j.1365-2125.2002.01618.x