Cytochrome P 450 2C9 phenotyping using low-dose tolbutamide

Jetter, Alexander; Kinzig‐Schippers, Martina; Skott, Andreas; Lazar, Andreas; Tomalik-Scharte, Dorota; Kirchheiner, Julia; Walchner-Bonjean, Monika; Hering, Ursula; Jakob, Verena; Rodamer, Michael; Jabrane, Wafaâ; Kasel, Dirk; Brockmöller, Jürgen; Fuhr, Uwe; Sörgel, Fritz

doi:10.1007/s00228-004-0754-z

Cited by 66 publications

(45 citation statements)

References 13 publications

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“…The quantification of phenotyping substrates (caffeine, tolbutamide, omeprazole, dextromethorphan, and midazolam) in plasma was performed using specific and sensitive liquid chromatography/tandem mass spectrometry methods as described earlier (Kasel et al, 2002;Jetter et al, 2004;Tomalik-Scharte et al, 2005;Frank et al, 2007; for specific details, see Zadoyan et al, 2012).…”

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confidence: 99%

Drug Cocktail Interaction Study on the Effect of the Orally Administered Lavender Oil Preparation Silexan on Cytochrome P450 Enzymes in Healthy Volunteers

et al. 2013

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This cocktail study evaluated the interaction potential of the oral lavender oil preparation silexan with major P450 (cytochrome P450) enzymes. Subjects and Methods: Sixteen healthy male or female Caucasians completed this double-blind, randomized, 2-fold crossover study. Silexan (160 mg) or placebo were administered once daily for 11 days. Additionally, on day 11 of both study periods, 150 mg caffeine (CYP1A2), 125 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan-HBr (CYP2D6), and 2 mg midazolam (CYP3A4) were administered orally. Formal interaction was excluded if the 90% confidence interval (CI) for the silexan over placebo ratios for phenotyping metrics (primary: AUC 0-t ) was within a 0.70-1.43 range. Results: According to the AUC 0-t comparisons, silexan had no relevant effect on CYP1A2, 2C9, 2D6, and 3A4 activity. Secondary phenotyping metrics confirmed this result. Mean ratios for all omeprazole-derived metrics were close to unity. The 90% CI for the AUC 0-t ratio of omeprazole but not for omeprazole/5-OH-omeprazole plasma ratio 3 hours post-dose or omeprazole/5-OH-omeprazole AUC 0-t ratio (secondary CYP2C19 metrics) was above the predefined threshold of 1.43, probably caused by the inherent high variability of omeprazole pharmacokinetics. Silexan and the phenotyping drugs were well tolerated. Repeated silexan (160 mg/day) administration has no clinically relevant inhibitory or inducing effects on the CYP1A2, 2C9, 2C19, 2D6, and 3A4 enzymes in vivo.

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confidence: 99%

Drug Cocktail Interaction Study on the Effect of the Orally Administered Lavender Oil Preparation Silexan on Cytochrome P450 Enzymes in Healthy Volunteers

et al. 2013

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“…16,17 Genotyping Genomic DNA was extracted from peripheral blood leukocytes by the standard salting-out method. 18 Genotyping of CYP2C9*2 (c.430C > T, rs1799853) and CYP2C9*3 (c.1075A>C, rs1057910) polymorphisms was detected by a polymerase chain reaction (PCR) followed by a restriction enzyme 19 and VKORC1 3673 (c.1639G > A, rs9923231) by PCR followed by high-resolution melting analysis (Rotor Gene 6000, Qiagen, Courtaboeuf, France), 13,20 according to the protocol previously described. …”

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confidence: 99%

Simultaneous Use of Amiodarone Influences Warfarin Maintenance Dose but Is Not Associated with Adverse Events

Santos¹,

Soares

Strunz³

et al. 2014

JMCP

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“…Venous blood samples were collected at 24 hours after administration of 125 mg tolbutamide orally. Plasma was isolated and stored at -80°C for long-term storage prior to analysis using liquid chromatography-mass spectrometry (Jetter et al, 2004). Genomic DNA was extracted from dried blood spots (Battaile et al, 2001) and genotyped for CYP2C9 alleles (*1, *2, and *3) using melt curve analysis (Hill et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

“…Demographic data were analyzed using descriptive statistics. The natural logarithm of tolbutamide concentration at 24 hours (C 24 ) was used as a metric of CYP2C9 status, based on the prior work by Jetter et al (2004). Equivalency of CYP2C9 status before and after treatment was tested based on the guidelines of US Food and Drug Administration (2003) and the European Medicines Agency (2010) using SigmaPlot software (version 11.0; Systat Software, Inc., San Jose, CA).…”

Section: Methodsmentioning

confidence: 99%

An Ethinyl Estradiol-Levonorgestrel Containing Oral Contraceptive Does Not Alter Cytochrome P4502C9 In Vivo Activity

et al. 2013

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Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug-drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies. In the current study, we examined the phenotypic status of CYP2C9 using low-dose (125 mg) tolbutamide before and after oral contraceptive use in reproductive age women. Blood was collected 24 hours after the tolbutamide oral dose was administered, plasma was isolated, and tolbutamide concentration (C 24 ) was measured using liquid chromatography-mass spectrometry. The natural logarithm of tolbutamide C 24 , a metric for CYP2C9 phenotype, was found to be equivalent (within 80%-125% equivalency boundaries) before and after oral contraceptive use. In conclusion, levonorgestrel-containing oral contraceptives, the most commonly used form of oral contraception, do not affect the status of the CYP2C9 enzyme. This suggests that it is safe to coadminister levonorgestrel-containing oral contraceptives and CYP2C9 substrates, which include a wide array of drugs.

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Cytochrome P 450 2C9 phenotyping using low-dose tolbutamide

Abstract: A low dose of 125 mg tolbutamide can safely and accurately be used for CYP2C9 phenotyping. As a simple metric for CYP2C9 activity, we propose to determine tolbutamide in plasma 24 h after drug intake.

Cited by 66 publications

References 13 publications

Drug Cocktail Interaction Study on the Effect of the Orally Administered Lavender Oil Preparation Silexan on Cytochrome P450 Enzymes in Healthy Volunteers

Drug Cocktail Interaction Study on the Effect of the Orally Administered Lavender Oil Preparation Silexan on Cytochrome P450 Enzymes in Healthy Volunteers

Simultaneous Use of Amiodarone Influences Warfarin Maintenance Dose but Is Not Associated with Adverse Events

An Ethinyl Estradiol-Levonorgestrel Containing Oral Contraceptive Does Not Alter Cytochrome P4502C9 In Vivo Activity

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