Clinical inhibition of CYP2D6-catalysed metabolism by the antianginal agent perhexiline.
OBJECTIVE
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.
Davies
Benjamin J L
BJ
Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville 5011, South Australia, Australia.
Coller
Janet K
JK
James
Heather M
HM
Gillis
David
D
Somogyi
Andrew A
AA
Horowitz
John D
JD
Morris
Raymond G
RG
Sallustio
Benedetta C
BC
D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000652:urine; D003917:Dextrorphan / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D010480:Perhexiline / Q000627:therapeutic use*
D002317:Cardiovascular Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003917:Dextrorphan; D003915:Dextromethorphan; D010480:Perhexiline