Clinical inhibition of CYP2D6‐catalysed metabolism by the antianginal agent perhexiline

Abstract

AimsPerhexiline is an antianginal agent that displays both saturable and polymorphic metabolism via CYP2D6. The aim of this study was to determine whether perhexiline produces clinically significant inhibition of CYP2D6-catalysed metabolism in angina patients. MethodsThe effects of perhexiline on CYP2D6-catalysed metabolism were investigated by comparing urinary total dextrorphan/dextromethorphan metabolic ratios following a single dose of dextromethorphan (16.4 mg) in eight matched control patients not taking perhexiline and 24 patients taking perhexiline. All of the patients taking perhexiline had blood drawn for CYP2D6 genotyping as well as to measure plasma perhexiline and cis -OH-perhexiline concentrations. ResultsMedian (range) dextrorphan/dextromethorphan metabolic ratios were significantly higher ( P < 0.0001) in control patients, 271.1 (40.3-686.1), compared with perhexiline-treated patients, 5.0 (0.3-107.9). In the perhexiline-treated group 10/24 patients had metabolic ratios consistent with poor metabolizer phenotypes; however, none was a genotypic poor metabolizer. Interestingly, 89% of patients who had phenocopied to poor metabolizers had only one functional CYP2D6 gene. There was a significant negative linear correlation between the log of the dextrorphan/dextromethorphan metabolic ratio and plasma perhexiline concentrations ( r 2 = 0.69, P < 0.0001). Compared with patients with at least two functional CYP2D6 genes, those with one functional gene were on similar perhexiline dosage reg imens but had significantly higher plasma perhexiline concentrations, 0.73 (0.21-1.00) vs. 0.36 (0.04-0.69) mg l -1 ( P = 0.04), lower cis -OH-perhexiline/perhexiline ratios, 2.85 (0.35-6.10) vs. 6.51 (1.84-11.67) ( P = 0.03), and lower dextrorphan/dextromethorphan metabolic ratios, 2. 51 (0.33-39.56) vs. 11.80 (2.90-36.93) ( P = 0.005). ConclusionsPerhexiline significantly inhibits CYP2D6-catalysed metabolism in angina patients. The plasma cis -OH-perhexiline/perhexiline ratio may help to both phenotype patients and predict those in whom perhexiline may be most likely to cause clinically significant metabolic inhibition. Clinical inhibition of CYP2D6 by perhexilineBr J Clin Pharmacol 57 :4 457

Effect of CYP2D6 metabolizer status on the disposition of the (+) and (−) enantiomers of perhexiline in patients with myocardial ischaemia

“…Several studies have previously reported that CYP2D6 metabolic capacity increases with the number of functional CYP2D6 genes [32,33] as a result of increased protein expression [32]. A similar effect of CYP2D6 genotype on the metabolism of rac-perhexiline has also been reported in several clinical studies that measured unresolved (+)-/(-)-perhexiline and cis-OH-perhexiline concentrations in plasma [22,34,35]. The importance of CYP2D6 in the metabolism of both (+) and (-)-perhexiline is further highlighted by the 94.3 and 91.1% lower median CL/F values, respectively, in phenotypic poor compared with extensive/intermediate metabolizers, suggesting that CYP2D6 is the major determinant of clearance for both enantiomers.…”

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

“…Eighteen caucasian patients admitted to the Cardiology Unit of The Queen Elizabeth Hospital gave written informed consent prior to participating in the study. Thirteen of these patients had previously participated in a group of 24 to study the effect of perhexiline on CYP2D6 activity assessed by dextromethorphan [11]. The patients were between 48 and 87 years of age upon entry to the study, with a mean (± SD) age of 73.0 ± 11.6 years.…”

“…Because the metabolic ratio reflects oral clearance, it can be used to guide perhexiline dosage, which can vary from 70 mg week −1 for PM up to 500 mg day −1 for UM [10]. In addition, the metabolic ratio may also be used to identify IM subjects who are likely to be more susceptible to significant interactions with CYP2D6 inhibitors due to diminished CYP2D6 metabolic capacity [11].…”

“…CYP2D6 expression increases with the number of functional CYP2D6 gene copies per genome [12] and is responsible for the gene–dose effect seen with respect to perhexiline metabolism [11, 13]. Increased gene copy number as a consequence of alleles containing multiple gene copies predicts only about 20% of all individuals with UM phenotype [14].…”

Cardiac metabolism — A promising therapeutic target for heart failure

“…Dose-titration for perhexiline is also necessitated by the potential for metabolic drug-drug interactions and ultra-rapid metabolism in some patients (Davies, et al, 2004).…”