Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose

Authors

  • Benedetta C. Sallustio,

    1. Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville 5011 and
    2. Department of Clinical and Experimental Pharmacology, The University of Adelaide, Adelaide 5000, South Australia
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  • Ian S. Westley,

    1. Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville 5011 and
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  • Raymond G. Morris

    1. Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville 5011 and
    2. Department of Clinical and Experimental Pharmacology, The University of Adelaide, Adelaide 5000, South Australia
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Dr Benedetta C. Sallustio, Clinical Pharmacology Laboratory, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville SA 5011, Australia. E-mail: benedetta.sallustio@nwahs.sa.gov.au

Abstract

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

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