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

Chong, Cher-Rin, Drury, Nigel E., Licari, Giovanni, Frenneaux, Michael P., Horowitz, John D., Pagano, Domenico and Sallustio, Benedetta C. (2015) Stereoselective handling of perhexiline:Implications regarding accumulation within the human myocardium. European Journal of Clinical Pharmacology, 71 (12). pp. 1485-1491. ISSN 0031-6970

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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.

Item Type: Article
Uncontrolled Keywords: perhexiline,metabolism,pharmacokinetics,drug uptake,stereoselectivity
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
Depositing User: Pure Connector
Date Deposited: 10 Feb 2016 15:00
Last Modified: 04 May 2023 23:58
DOI: 10.1007/s00228-015-1934-8


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