Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose.
OBJECTIVE
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.
Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville 5011, South Australia. benedette.sallustio@nwahs.sa.gov.au
Benedetta C
BC
Sallustio
Ian S
IS
Westley
Raymond G
RG
Morris
D000787:Angina Pectoris / Q000097:blood / Q000188:drug therapy*; D001682:Biological Availability; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D010480:Perhexiline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010641:Phenotype; D012189:Retrospective Studies; D012680:Sensitivity and Specificity
D002317:Cardiovascular Agents; D019389:Cytochrome P-450 CYP2D6; D010480:Perhexiline