Application of microdosed intravenous omeprazole to determine hepatic CYP2C19 activity.

2020 
Omeprazole is an established probe drug to assess cytochrome P450 (CYP) 2C19 activity (phenotyping). Because it has non-linear pharmacokinetics (PK) after oral administration (auto-inhibition of metabolism), the true impact of co-administered perpetrators on CYP2C19 substrates might be underestimated after regular doses. We tested the dose-linearity of an intravenous (IV) omeprazole microdose of 100 μg and compared it with a 20-mg dose in 4 healthy poor (PMs) and 6 extensive CYP2C19 metabolizers (EMs) in the presence and absence of a strong inhibitor (voriconazole). Without voriconazole, omeprazole exposure was dose-proportional irrespective of the genotype but in PMs geometric mean ratios (GMR) of AUC0-∞ were 6.6-fold higher and molar metabolic ratios of 5-OH omeprazole/omeprazole approximately 10-fold lower. Voriconazole increased omeprazole exposure in EMs approximately 5-fold (GMR AUC0-4 (90% CI) after 100 μg omeprazole: 4.61 (2.69,7.89), after 20 mg omeprazole: 5.5 (1.07,1.46)), whereas no clinically significant impact on PK in PMs was observed (GMR AUC0-4 (90%-CI) after 100 μg omeprazole: 1.29 (0.81,2.04), after 20 mg omeprazole: 1.25 (1.07,1.46)). Linear regression and Bland-Altman analyses revealed an excellent agreement between AUC0-∞ and AUC0-4 of omeprazole (r2 = 0.987; bias [%], 95 %-CI: 0.35, -3.197-3.89) and also the molar metabolic ratio (5-OH omeprazole/omeprazole) (r2 = 0.987; -3.939, -9.06-1.18), suggesting that an abbreviated sampling protocol can be used for IV CYP2C19 phenotyping and drug interaction studies. In conclusion, the PK of IV omeprazole microdoses closely reflect the changes observed with regular omeprazole doses, however, to avoid auto-inhibition of probe drugs, microdosing appears to be the favorable technique. This article is protected by copyright. All rights reserved.
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