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Clinical inhibition of CYP2D6‐catalysed metabolism by the antianginal agent perhexiline
Author(s) -
Davies Benjamin J. L.,
Coller Janet K.,
James Heather M.,
Gillis David,
Somogyi Andrew A.,
Horowitz John D.,
Morris Raymond G.,
Sallustio Benedetta C.
Publication year - 2004
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2003.02033.x
Subject(s) - dextromethorphan , dextrorphan , cyp2d6 , pharmacology , medicine , pharmacokinetics , metabolism , cytochrome p450
Aims Perhexiline 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. Methods The 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. Results Median (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 regimens 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). Conclusions Perhexiline 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.