Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity.
Eur J Clin Pharmacol
; 64(4): 387-98, 2008 Apr.
Article
en En
| MEDLINE
| ID: mdl-18071681
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oxidorreductasas N-Desmetilantes
/
Hidrocarburo de Aril Hidroxilasas
/
Mefenitoína
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Anticonvulsivantes
Tipo de estudio:
Clinical_trials
Límite:
Adult
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Eur J Clin Pharmacol
Año:
2008
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Alemania