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.
Sallustio
Benedetta C
BC
Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville 5011, South Australia. benedette.sallustio@nwahs.sa.gov.au
Westley
Ian S
IS
Morris
Raymond G
RG
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