Aims 1) To develop an estimate of oral clearance ( /F) for the antianginal agent perhexiline based on the ratio of cis-OH-perhexiline metabolite/parent perhexiline plasma concentrations at steady-state . 2) To determine whether the ratio measured in the first fortnight of treatment 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 /F and / were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by /F≤50 ml min−1 or /≤0.3. A group of patients with /F≥950 ml min−1 may have been ultra-rapid metabolizers. In this group, the high /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 /F (r2=0.741, P<0.0001). Study 2 (n=23). Using / patients were tentatively identified as poor, extensive and ultra-rapid metabolizers, with /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.