ARTICLE IN PRESS HLC-1484; No. of Pages 3 BRIEF COMMUNICATION Brief Communication Interaction of Terbinafine (Anti-fungal agent) with Perhexiline: A Case Report Abdul Rauf Sheikh a,b , Ian Westley c,e , Benedetta Sallustio c,d , John D Horowitz a,b and John F Beltrame a,b,* a The Discipline of Medicine, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia b Cardiology Unit, The Queen Elizabeth Hospital, Central Adelaide Local Health Network c Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Central Adelaide Local Health Network d The Discipline of Pharmacology, The University of Adelaide, Adelaide, South Australia e School of Pharmacy and Medical Sciences, University of South Australia, South Australia Abstract: Perhexiline is a unique anti-anginal agent that is frequently used in the treatment of chronic refractory angina. Its utility has been limited because of its complex pharmacokinetics that were only appreciated following the development of a therapeutic perhexiline assay. Perhexiline is cleared primarily via formation of mono-hydroxy metabolites (OH-perhexiline) by cytochrome P450 2D6 (CYP2D6). Drugs that are inhibitors of CYP2D6 may therefore inhibit perhexiline metabolism, increase plasma perhex- iline concentration and may consequently increase the risk of toxicity. We report a case of a rise in perhexiline plasma concentration to a toxic level following the introduction of terbinafine hydrochloride; a moderate CYP2D6 inhibiting drug. (Heart, Lung and Circulation 2013;xxx:1–3) Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved. Keywords. Perhexiline; Terbinafine; Cytochrome P450 2D6 (CYP2D6); Selective serotonin re-uptake inhibitors (SSRIs) Introduction P erhexiline was first introduced in the 1970s as an effec- tive anti-anginal [1] but was abandoned by many clinicians due to unexpected adverse effects with its chronic use; including hepato- and neurotoxicity. With the development of a perhexiline plasma assay, its complex pharmacokinetics were appreciated (especially in relation to slow metabolisers) thereby permitting rational pre- scription of this effective anti-anginal. In recent times its use has experienced resurgence, particularly considering the lack of adverse haemodynamic effects and its apparent benefit in heart failure [3], hypertrophic cardiomyopathy and aortic stenosis [2], as well as its established efficacy in chronic refractory angina [3]. These beneficial effects are attributable to its improvement in myocardial energetics by enhancing myocardial glucose utilisation and thus an oxygen–sparing effect. Received 17 August 2013; received in revised form 19 November 2013; accepted 29 November 2013 * Corresponding author. Discipline of Medicine, The University of Adelaide, The Queen Elizabeth Hospital, 28- Woodville Rd, Woodville South, South Australia 5011, Australia. Tel.: +61 8 82226740; fax: +61 8 82227201. E-mail address: john.beltrame@adelaide.edu.au (J.F. Beltrame). Considering that the efficacy and toxicity of perhexi- line are dependent on plasma/tissue drug concentrations, therapeutic drug monitoring is necessary to minimise the risk of severe adverse events whilst still main- taining maximal anti-anginal benefits during long term therapy.[4] Adverse effects (such as abnormal liver func- tion tests, nausea, ataxia and hypoglycaemia) are seen when serum perhexiline concentrations exceed 0.60 mg/L. [5] Perhexiline is cleared primarily via formation of mono- hydroxy metabolites (OH-perhexiline) by cytochrome P450 2D6 (CYP2D6), which displays genetic polymor- phism. Approximately 5-10% of Caucasians lack the functional enzyme and are “poor metabolisers”, usually clearing perhexiline at approximately 10% of the rate of extensive metabolisers, thus requiring a weekly dose of 50–100 mg compared with the conventional daily dose of 100–200 mg in extensive metabolisers. A small percent- age of patients are ultra-rapid CYP2D6 metabolisers and require increased steady-state doses of perhexiline (up to 500 mg/day).[6] The ratio of plasma OH-perhexiline: per- hexiline concentrations may be used as a guide to CYP2D6 metaboliser phenotype, with a ratio <0.3 indicating poor metabolisers. To further complicate the pharmacokinetic attributes of this agent, it exhibits non-linear kinetics, so that a small dosage change may result in a major change Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved. 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.11.012 Please cite this article in press as: Sheikh AR, et al. Interaction of Terbinafine (Anti-fungal agent) with Perhexiline: A Case Report. Heart Lung Circulation 2013, http://dx.doi.org/10.1016/j.hlc.2013.11.012