Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity.
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 optima...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 64; no. 4; pp. 387 - 399 |
|---|---|
| Autores principales: | , , , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Springer Nature
Apr2008
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=105650107&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 105650107 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Apr2008 vid: 64 iid: 4 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 105650107 2009819063 10.1007/s00228-007-0416-z NLM18071681 105650107 ppf: 387 ppct: 12 formats: fmt: @attributes: type: P tig: atl: Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity. aug: au: Klaassen T Jetter A Tomalik-Scharte D Kasel D Kirchheiner J Jaehde U Fuhr U affil: Department of Pharmacology, Clinical Pharmacology, Hospital of the University of Cologne, Gleueler Str. 24, 50931 Köln, Germany. sug: subj: Enzymes Physiology Phenotype Phenytoin Urine Descriptive Statistics Male Urinalysis Methods White Persons Human Male ab: 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. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|