Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: comparison of sparteine and dextromethorphan.
OBJECTIVE
To examine whether the variability of CYP2D6 activity in patients with chronic renal failure can be assessed, particularly among subjects with the extensive metabolizer phenotype, by use of standard in vivo indexes of CYP2D6 activity derived from oral administration of dextromethorphan and sparteine.


METHODS
A single 100 mg oral dose of sparteine and a single 40 mg oral dose of dextromethorphan were administered on two occasions to 12 patients with chronic renal failure (creatinine clearance ranging from 20 to 70 ml/min) and 12 age- and sex-matched healthy subjects. Sparteine clearances, sparteine metabolic ratio, and urinary recovery of dextrorphan were calculated. Patients and healthy control subjects were not selected on the basis of their CYP2D6 phenotypes.


RESULTS
Chronic renal failure was associated with a decrease in sparteine partial metabolic clearance to dehydrosparteine (median of 322 ml/min and range of 62 to 670 ml/min in patients with renal failure versus median of 635 ml/min and range of 77 to 1276 ml/min in normal subjects; p < 0.02). Sparteine apparent oral clearance (p < 0.03) and renal clearance (p < 0.001) decreased in patients with renal failure. However, sparteine metabolic ratio was not significantly altered in patients with renal failure and showed that all patients were extensive metabolizers of sparteine. Although fractional urinary excretion of dextrorphan decreased in patients with renal failure (median, 24.4%; range, 9.7% to 55.9%) compared with control (median, 47.5%; range, 24.1% to 72.1%) (p = 0.02), it also showed that all subjects were extensive metabolizers of dextromethorphan. The amount of dextromethorphan excreted in urine correlated with creatinine clearance independently from CYP2D6 activity measured as sparteine partial metabolic clearance. However, it did not correlate with sparteine metabolic ratio or with fractional urinary excretion of dehydrosparteine.


CONCLUSIONS
Assessment of CYP2D6 activity by use of dextromethorphan and sparteine is possible in extensive metabolizer patients with chronic renal failure. However, in these subjects, dextromethorphan and sparteine do not reflect CYP2D6 activity in the same way.
Kévorkian
J P
JP
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
Michel
C
C
Hofmann
U
U
Jacqz-Aigrain
E
E
Kroemer
H K
HK
Peraldi
M N
MN
Eichelbaum
M
M
Jaillon
P
P
Funck-Brentano
C
C
D000284:Administration, Oral; D000328:Adult; D000996:Antitussive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D003404:Creatinine / Q000652:urine; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000201:enzymology* / Q000652:urine; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010120:Oxytocics / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D010641:Phenotype; D012044:Regression Analysis; D013034:Sparteine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine
D000996:Antitussive Agents; D010120:Oxytocics; D013034:Sparteine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6