Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans

Annika Elbe,Peter Rose,Jürgen Burhenne,Kathrin Isabelle Foerster,Gerd Mikus,Walter Emil Haefeli,Antje Blank

doi:10.1007/s00228-022-03304-3

Abstract

PurposeTo investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine.MethodsAn open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction). To prevent degradation of the uncoated omeprazole microdose, sodium bicarbonate buffer was administered. The pharmacokinetics of omeprazole and its 5-hydroxy-metabolite were assessed as well as the pharmacokinetics of midazolam and yohimbine to estimate CYP3A4 and CYP2D6 activity.ResultsCalculated pharmacokinetic parameters after administration of 100 µg and 20 mg omeprazole in healthy subjects suggest dose proportionality. Omeprazole clearance was significantly decreased by fluconazole from 388 [95% CI: 266–565] to 47.2 [42.8–52.0] mL/min after 20 mg omeprazole and even further after 100 µg omeprazole (29.4 [24.5–35.1] mL/min). Rifampicin increased CYP2C19-mediated omeprazole metabolism. The omeprazole hydroxylation index was significantly related to omeprazole clearance for both doses. Both fluconazole and rifampicin altered CYP3A4 activity whereas no change of CYP2D6 activity was observed at all.ConclusionsMicrodosed oral omeprazole is suitable to determine CYP2C19 activity, also during enzyme inhibition and induction. However, the administration of sodium bicarbonate buffer also had a small influence on all victim drugs used.Trial registrationEudraCT: 2017–004270-34.

Highlights

Cytochrome P450 2C19 (CYP2C19) is an important enzyme of the cytochrome P450 enzyme family with large interindividual differences in the CYP2C19 activity due to genetic polymorphisms [1]
We investigated whether microdosed oral omeprazole is suitable to determine CYP2C19 activity in vivo in comparison to a therapeutic dose, under conditions of CYP2C19 inhibition and induction
CYP2C19 induction and inhibition were reflected in all other pharmacokinetic parameters, with omeprazole clearance decreasing significantly by 88% during fluconazole and increasing 11-fold during rifampicin (Table 1)

Summary

Introduction

Cytochrome P450 2C19 (CYP2C19) is an important enzyme of the cytochrome P450 enzyme family with large interindividual differences in the CYP2C19 activity due to genetic polymorphisms [1]. These differences in activity result in high interindividual variability of the metabolism of proton pump inhibitors (e.g., omeprazole), antiepileptic agents (e.g., brivaracetam, barbiturates, phenytoin), antiplatelet drugs (e.g., clopidogrel), and antidepressants (e.g., citalopram) [2–4]. An exploratory study with some major limitations (small sample size, no CYP2C19 genotyping performed) was published in which 100 μg omeprazole was orally administered to explore the applicability of a microdose in a drug-drug interaction (DDI) trial [12]. Microdosed intravenous omeprazole has been shown to represent hepatic CYP2C19 activity recently [13]

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Conclusion