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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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 β-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 β-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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Acknowledgements

The technical and administrative assistance of Steffi Harlfinger, Dorothee Frank, Ingrid Fehrenz and Gregor Zadoyan are gratefully acknowledged. The authors state that they have no conflict of interest relevant to the contents of this manuscript.

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Author notes

  1. Alexander Jetter

    Present address: Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zurich, Zürich, Switzerland

  2. Dirk Kasel

    Present address: Department of Pharmacokinetics, Grünenthal GmbH, Aachen, Germany

Authors and Affiliations

  1. Department of Pharmacology, Clinical Pharmacology, Hospital of the University of Cologne, Gleueler Str. 24, 50931, Köln, Germany

    Tobias Klaassen, Alexander Jetter, Dorota Tomalik-Scharte, Dirk Kasel & Uwe Fuhr

  2. Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany

    Julia Kirchheiner

  3. Department of Clinical Pharmacy, University of Bonn, Bonn, Germany

    Ulrich Jaehde

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  1. Tobias Klaassen
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Correspondence to Uwe Fuhr.

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Klaassen, T., Jetter, A., Tomalik-Scharte, D. et al. Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity. Eur J Clin Pharmacol 64, 387–398 (2008). https://doi.org/10.1007/s00228-007-0416-z

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