Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

作者：Klaassen Tobias; Jetter Alexander; Tomalik Scharte Dorota; Kasel Dirk; Kirchheiner Julia; Jaehde Ulrich; Fuhr Uwe^*

来源：European Journal of Clinical Pharmacology, 2008, 64(4): 387-398.

DOI：10.1007/s00228-007-0416-z

• cumulative and fractionated urine collection
• CYP2B6
• CYP2C19 metrics
• 4 '-hydroxymephenytoin
• (S)-mephenytoin
• nirvanol
• phenotyping cocktail

Objectives (S)-Mephenytoin is selectively metabolised to (S)-4'-hydroxymephenytoin by CYP2C19. The urinary excretion of 4'-hydroxymephenytoin reflects the activity of individual enzymes. We evaluated fractioned urinary collection and beta-glucuronidase pre-treatment in order to determine the optimal CYP2C19 metrics. We also assessed whether urinary excretion of N-desmethylmephenytoin (nirvanol) might be a useful CYP2B6 metric in in vivo studies.
Methods A 50-mg dose of mephenytoin was administered to 52 volunteers as a component of phenotyping cocktails in four separate studies. Urine was collected up to 166 h post-dose. Urinary excretion of 4'-hydroxymephenytoin and nirvanol was quantified by liquid chromatography-tandem mass spectrometry, and common CYP2C19 and CYP2B6 genotypes were determined.
Results Cumulative excretion of 4'-hydroxymephenytoin in urine with beta-glucuronidase treatment collected from before mephenytoin administration up to 12-16 h thereafter showed the greatest difference between CYP2C19 genotypes and the lowest intra-individual variability (7%). Renal elimination of nirvanol was highest for a *44 individual and lowest for individuals carrying the *55 and *17 genotype, but lasted for several weeks, thus making its use in cross-over studies difficult.
Conclusion Cumulative urinary excretion of 4'-hydroxymephenytoin 0-12 h post-administration is a sensitive and reproducible metric of CYP2C19 activity, enabling the effect of a drug on CYP2C19 to be assessed in a small sample size of n=6 volunteers. While nirvanol excretion may reflect CYP2B6 activity in vivo, it is not useful for CYP2B6 phenotyping.

• 出版日期2008-4