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Assessment of Urinary Mephenytoin Metrics to Phenotype for CYP2C19 and CYP2B6 Activity

Assessment of Urinary Mephenytoin Metrics to Phenotype for CYP2C19 and CYP2B6 Activity

Tobias Klaassen, Alexander Jetter, Dorota Tomalik-Scharte, Dirk Kasel, Julia Kirchheiner, Ulrich Jaehde, Uwe Fuhr

Eur J Clin Pharmacol. 2008 Apr;64(4):387-98.

PMID: 18071681

Abstract:

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 *4/*4 individual and lowest for individuals carrying the *5/*5 and *1/*7 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP65567342	(S)-(+)-Nirvanol		65567-34-2	Price

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