Mephenytoin as a probe for CYP2C19 phenotyping:effect of sample storage, intra‐individual reproducibility and occurrence of adverse events

Tamminga, Wim J.; Wemer, J.; Oosterhuis, B.; Wieling, Jaap; Touw, Daan; Zeeuw, Rokus A. de; Leij, Lou F. M. H. de; Jonkman, J. H. G.

doi:10.1046/j.1365-2125.2001.01331.x

Cited by 14 publications

(17 citation statements)

References 8 publications

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“…Smephenytoin, proguanil, and omeprazole have been suggested and used for phenotyping CYP2C19 [17,[31][32][33][34]. Very recently, [ 13 C]-pantoprazole breath test was proposed as a method for identifying CYP2C19 activity [35].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype–phenotype correlation in childhood

Gümüş

Karaca

Babaoğlu

et al. 2011

Eur J Clin Pharmacol

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Section: Discussionmentioning

confidence: 99%

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype–phenotype correlation in childhood

Gümüş

Karaca

Babaoğlu

et al. 2011

Eur J Clin Pharmacol

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“…Mephenytoin as a probe drug for CYP2C19 is well established and used in epidemiological studies as well as in clinical pharmacological research (Tamminga et al, 2001). Urinary recovery of 4Ј-hydroxymephenytoin in an 8-h urine sample has been shown to discriminate precisely between poor and extensive metabolizers of mephenytoin (Wedlund et al, 1984(Wedlund et al, , 1985.…”

Section: Downloaded Frommentioning

confidence: 99%

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers

Tomalik-Scharte

Jetter²,

Kinzig‐Schippers³

et al. 2005

Drug Metabolism and Disposition

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ABSTRACT:The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam Propiverine hydrochloride, described below as propiverine, is indicated for the treatment of urinary incontinence, as well as urinary urgency and frequency in patients who have either idiopathic detrusor overactivity (overactive bladder) or neurogenic detrusor overactivity (detrusor hyperreflexia) from spinal cord injuries, e.g., transverse lesion paraplegia. It exhibits antagonistic effects toward muscarinic acetylcholine receptors and calcium channel-modulating properties (Siegmund et al., 1990;Yono et al., 1999;Madersbacher and Mürtz, 2001).After oral administration, propiverine is rapidly and almost completely absorbed from the gastrointestinal tract. The maximal serum concentration is reached approximately 90 min after a single dose of 15 mg. Propiverine undergoes extensive presystemic metabolism via N-oxidation to propiverine-N-oxide with involvement of cytochrome P450 enzymes. Mean elimination half-life after chronic administration of propiverine is about 15 h. The major fraction of propiverine and its metabolites is eliminated in the urine (Haustein and Hüller, 1988;Siepmann et al., 1998). Information on the enzymes mediating phase I metabolism of propiverine has been obtained in several in vitro systems (APOGEPHA, data on file). The primary metabolic route involves the oxidation of the piperidyl-N and is mediated by CYP3A4 and flavin-containing monoxygenases 1 and 3, and leads to the formation of the much less active N-oxide. CYP2C9 and CYP2C19 may also mediate a fraction of overall propiverine elimination, whereas other enzymes (e.g., CYP1A2 and CYP2D6) were involved to a minor extent.Several studies concerning possible drug-drug interactions of propiverine have been published. Müller et al. (1993) demonstrated that there is no effect of the CYP2D6 genotype on propiverine biotransformation in humans, so that no effect of CYP2D6 inhibitors on propiverine pharmacokinetics is expected. Results of a study performed in rats provided no evidence for propiverine to cause relevant drug-drug interactions (Borchert et al., 1986). Studies on the effect of propiverine on drug-metabolizing enzymes in human and rat hepatocyte cultures demonstrated an increase in CYP3A4 mRNA and This study was supported by APOGEPHA Arzneimittel GmbH, Dresden, Germany.Article, publication date, and citation information can be found at

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“…The S/R ratio is affected by instability of a (S)-mephenytoin cysteine conjugate, exclusively found in the urine of EM, resulting in an increase in (S)-mephenytoin concentrations during sample storage in the freezer. 7,8 Therefore, we selected the urinary recovery of 4 0 -hydroxymephenytoin as the metric of choice and examined both, the free and glucuronidated metabolite. Although the role of CYP2B6 in formation of (R)-nirvanol is well established, it is still not known whether it provides appropriate metrics to estimate CYP2B6 activity.…”

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confidence: 99%

Quantification of mephenytoin and its metabolites 4′‐hydroxymephenytoin and nirvanol in human urine using a simple sample processing method

Klaassen

Kasel

Harlfinger

et al. 2004

Rapid Comm Mass Spectrometry

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A reliable and easy to use liquid chromatography/tandem mass spectrometry (LC/MS/MS) method without the use of sample extraction was developed for the simultaneous quantification of urinary concentrations of mephenytoin, a standard phenotyping substrate for the cytochrome P450 enzyme CYP2C19, and its phase I metabolites 4'-hydroxymephenytoin and nirvanol. Fifty microL of urine were diluted with a buffered beta-glucuronidase solution and incubated at 37 degrees C for 6 h followed by addition of methanol, containing the internal standard 4'-methoxymephenytoin. The chromatographic separation was achieved using a 100 x 3 mm, 5 micro Thermo Electron Aquasil C18 column with a gradient flow, increasing the organic fraction (acetonitrile/methanol 50:50) of the mobile phase from 10 to 90%. Quantification by triple-stage mass spectrometry (TSQ Quantum, Thermo Electron) was accomplished by negative electrospray ionization in the selected reaction monitoring mode. Linearity was observed for all substances in the concentration range 15-10 000 ng/mL. The lower limit of quantification (LLOQ) was 20 ng/mL for 4'-hydroxymephenytoin and 30 ng/mL for nirvanol and mephenytoin, respectively. Intra- and inter-day inaccuracy did not exceed 9.5% for all substances from LLOQ to 10 000 ng/mL. Intra- and inter-day precision were in the range of 0.8-10.5%. The method was validated according to international ICH and FDA guidelines and successfully applied for phenotyping of Caucasian male volunteers who received an oral dose of 50 mg mephenytoin.

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Mephenytoin as a probe for CYP2C19 phenotyping:effect of sample storage, intra‐individual reproducibility and occurrence of adverse events

Cited by 14 publications

References 8 publications

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype–phenotype correlation in childhood

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype–phenotype correlation in childhood

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers

Quantification of mephenytoin and its metabolites 4′‐hydroxymephenytoin and nirvanol in human urine using a simple sample processing method

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