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Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium.

Method

Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses.

Results

Myocardial uptake of both (+) and (−) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (−) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (−) perhexiline were the plasma concentrations [(+) perhexiline: β = −0.256, p = 0.015; (−) perhexiline: β = −0.347, p = 0.001] and patients’ age [(+) perhexiline: β = 0.300, p = 0.004; (−) perhexiline: β = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (β = 0.228, p = 0.025), while atrial uptake of (−) perhexiline varied inversely with simultaneous heart rate (β = −0.240, p = 0.015).

Conclusion

(1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (−) perhexiline may selectively modulate heart rate reduction.

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Acknowledgments

This project was supported by a project grant from the British Heart Foundation (PG/06/044/20703). C-RC is a recipient of a National Health and Medical Research Council (NHMRC) of Australia postgraduate scholarship. NED was also funded by a training award from the Wellcome Trust and a research grant from the Queen Elizabeth Hospital Birmingham Charity.

Disclosure

MPF is inventor of the method of use patents for perhexiline in heart muscle diseases. GL and BCS are inventors of patent for use of enantiomers of perhexiline.

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    Authors and Affiliations

    1. Cardiology and Clinical Pharmacology Departments, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, South Australia, Australia

      Cher-Rin Chong, Nigel E. Drury, Giovanni Licari, John D. Horowitz & Benedetta C. Sallustio

    2. Medicine, University of Adelaide, Adelaide, South Australia, Australia

      Cher-Rin Chong & John D. Horowitz

    3. Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK

      Nigel E. Drury & Domenico Pagano

    4. School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK

      Nigel E. Drury & Domenico Pagano

    5. Norwich Medical School, University of East Anglia, Norwich, UK

      Michael P. Frenneaux

    6. Pharmacology, University of Adelaide, Adelaide, South Australia

      Giovanni Licari & Benedetta C. Sallustio

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    1. Cher-Rin Chong
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    Correspondence to Benedetta C. Sallustio.

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    Cher-Rin Chong and Nigel E. Drury contributed equally to this work.

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    Chong, CR., Drury, N.E., Licari, G. et al. Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium. Eur J Clin Pharmacol 71, 1485–1491 (2015). https://doi.org/10.1007/s00228-015-1934-8

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    • DOI: https://doi.org/10.1007/s00228-015-1934-8

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