European Journal of Clinical Pharmacology

, Volume 71, Issue 12, pp 1485–1491 | Cite as

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

  • Cher-Rin Chong
  • Nigel E. Drury
  • Giovanni Licari
  • Michael P. Frenneaux
  • John D. Horowitz
  • Domenico Pagano
  • Benedetta C. Sallustio
Pharmacokinetics and Disposition

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.

Keywords

Perhexiline Metabolism Pharmacokinetics Drug uptake Stereoselectivity 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Cher-Rin Chong
    • 1
    • 2
  • Nigel E. Drury
    • 1
    • 3
    • 4
  • Giovanni Licari
    • 1
    • 6
  • Michael P. Frenneaux
    • 5
  • John D. Horowitz
    • 1
    • 2
  • Domenico Pagano
    • 3
    • 4
  • Benedetta C. Sallustio
    • 1
    • 6
  1. 1.Cardiology and Clinical Pharmacology DepartmentsBasil Hetzel Institute, Queen Elizabeth HospitalWoodville SouthAustralia
  2. 2.MedicineUniversity of AdelaideAdelaideAustralia
  3. 3.Department of Cardiothoracic SurgeryQueen Elizabeth Hospital BirminghamBirminghamUK
  4. 4.School of Clinical & Experimental MedicineUniversity of BirminghamBirminghamUK
  5. 5.Norwich Medical SchoolUniversity of East AngliaNorwichUK
  6. 6.PharmacologyUniversity of AdelaideAdelaideSouth Australia

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