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



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.


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.


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).


(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.


Perhexiline Metabolism Pharmacokinetics Drug uptake Stereoselectivity 


  1. 1.
    Kennedy JA, Unger SA, Horowitz JD (1996) Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol 52:273–280CrossRefPubMedGoogle Scholar
  2. 2.
    Roberts LN, Mason GP (1972) Clinical trial of a new antianginal drug: perhexiline maleate. J Clin Pharmacol New Drugs 12:342–348CrossRefPubMedGoogle Scholar
  3. 3.
    Burns-Cox CJ, Chandrasekhar KP, Ikram H, Peirce TH, Pilcher J, Quinlan CD et al (1971) Clinical evaluation of perhexiline maleate in patients with angina pectoris. Br Med J 4:586–588PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Bourrat C, Viala JJ, Guastala JP (1975) Letter: peripheral neuropathy after prolonged adsorption of perhexiline maleate. 2 cases. Nouv Presse Med 4:2528PubMedGoogle Scholar
  5. 5.
    Fraser DM, Campbell IW, Miller HC (1977) Peripheral and autonomic neuropathy after treatment with perhexiline maleate. Br Med J 2:675–676PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Le Menn G, Mabin D, Penther P (1977) Slow and incomplete regression of peripheral neuropathy due to perhexiline maleate. Ann Cardiol Angeiol (Paris) 26:149–150Google Scholar
  7. 7.
    Singlas E, Goujet MA, Simon P (1978) Pharmacokinetics of perhexiline maleate in anginal patients with and without peripheral neuropathy. Eur J Clin Pharmacol 14:195–201CrossRefPubMedGoogle Scholar
  8. 8.
    Cooper RG, Evans DA, Whibley EJ (1984) Polymorphic hydroxylation of perhexiline maleate in man. J Med Genet 21:27–33PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Barclay ML, Sawyers SM, Begg EJ, Zhang M, Roberts RL, Kennedy MA et al (2003) Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status. Pharmacogenetics 13:627–632CrossRefPubMedGoogle Scholar
  10. 10.
    Cole PL, Beamer AD, McGowan N, Cantillon CO, Benfell K, Kelly RA et al (1990) Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation 81:1260–1270CrossRefPubMedGoogle Scholar
  11. 11.
    Horowitz JD, Sia ST, Macdonald PS, Goble AJ, Louis WJ (1986) Perhexiline maleate treatment for severe angina pectoris—correlations with pharmacokinetics. Int J Cardiol 13:219–229CrossRefPubMedGoogle Scholar
  12. 12.
    Beadle RM, Frenneaux M (2010) Modification of myocardial substrate utilisation: a new therapeutic paradigm in cardiovascular disease. Heart 96:824–830CrossRefPubMedGoogle Scholar
  13. 13.
    Sallustio BC, Westley IS, Morris RG (2002) Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose. Br J Clin Pharmacol 54:107–114PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Philpott A, Chandy S, Morris R, Horowitz JD (2004) Development of a regimen for rapid initiation of perhexiline therapy in acute coronary syndromes. Intern Med J 34:361–363CrossRefPubMedGoogle Scholar
  15. 15.
    Stewart S, Voss DW, Northey DL, Horowitz JD (1996) Relationship between plasma perhexiline concentration and symptomatic status during short-term perhexiline therapy. Ther Drug Monit 18:635–639CrossRefPubMedGoogle Scholar
  16. 16.
    Liberts EA, Willoughby SR, Kennedy JA, Horowitz JD (2007) Effects of perhexiline and nitroglycerin on vascular, neutrophil and platelet function in patients with stable angina pectoris. Eur J Pharmacol 560:49–55CrossRefPubMedGoogle Scholar
  17. 17.
    Drury NE, Howell NJ, Calvert MJ, Weber RJ, Senanayake EL, Lewis ME et al (2015) The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial. Eur J Cardiothorac Surg 47(3):464–472PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Drury NE, Licari G, Chong CR, Howell NJ, Frenneaux MP, Horowitz JD et al (2014) Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake. Br J Clin Pharmacol 77:789–795PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Davies BJ, Coller JK, James HM, Somogyi AA, Horowitz JD, Sallustio BC (2006) The influence of CYP2D6 genotype on trough plasma perhexiline and cis-OH-perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia. Br J Clin Pharmacol 61:321–325PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Davies BJ, Coller JK, Somogyi AA, Milne RW, Sallustio BC (2007) CYP2B6, CYP2D6, and CYP3A4 catalyze the primary oxidative metabolism of perhexiline enantiomers by human liver microsomes. Drug Metab Dispos 35:128–138CrossRefPubMedGoogle Scholar
  21. 21.
    Gould BJ, Amoah AG, Parke DV (1986) Stereoselective pharmacokinetics of perhexiline. Xenobiotica 16:491–502CrossRefPubMedGoogle Scholar
  22. 22.
    Licari G, Sallustio BC, Somogyi AA, Milne RW (2014) The enantiomers of the myocardial metabolic agent perhexiline display divergent effects on hepatic energy metabolism and peripheral neural function in rats. Global Heart 9:e272CrossRefGoogle Scholar
  23. 23.
    Davies BJ, Herbert MK, Culbert JA, Pyke SM, Coller JK, Somogyi AA et al (2006) Enantioselective assay for the determination of perhexiline enantiomers in human plasma by liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 832:114–120CrossRefPubMedGoogle Scholar
  24. 24.
    Legato MJ (1973) Ultrastructure of the atrial, ventricular, and Purkinje cell, with special reference to the genesis of arrhythmias. Circulation 47:178–189CrossRefPubMedGoogle Scholar
  25. 25.
    Deschamps D, DeBeco V, Fisch C, Fromenty B, Guillouzo A, Pessayre D (1994) Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions. Hepatology 19:948–961CrossRefPubMedGoogle Scholar
  26. 26.
    Ling LH, Chik W, Averbuj P, Pati PK, Sverdlov AL, Ngo DT et al (2011) Effects of aging, renal dysfunction, left ventricular systolic impairment, and weight on steady state pharmacokinetics of perhexiline. Ther Drug Monit 33:251–256PubMedGoogle Scholar
  27. 27.
    Horowitz JD, Powell AC (1986) Myocardial uptake of drugs and clinical effects. Clin Pharmacokinet 11:354–371CrossRefPubMedGoogle Scholar
  28. 28.
    Barry WH, Horowitz JD, Smith TW (1985) Comparison of negative inotropic potency, reversibility, and effects on calcium influx of six calcium channel antagonists in cultured myocardial cells. Br J Pharmacol 85:51–59PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Ono H, Kimura M (1981) Effect of Ca2+-antagonistic vasodilators, diltiazem, nifedipine, perhexiline and verapamil, on platelet aggregation in vitro. Arzneimittelforschung 31:1131–1134PubMedGoogle Scholar
  30. 30.
    Abozguia K, Elliott P, McKenna W, Phan TT, Nallur-Shivu G, Ahmed I et al (2010) Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 122:1562–1569CrossRefPubMedGoogle Scholar
  31. 31.
    Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L et al (2005) Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation 112:3280–3288CrossRefPubMedGoogle Scholar

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

Personalised recommendations