Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity

Abstract

Omeprazole is an established probe drug to assess cytochrome P450 (CYP) 2C19 activity (phenotyping). Because it has nonlinear pharmacokinetics (PK) after oral administration (autoinhibition of metabolism), the true impact of coadministered perpetrators on CYP2C19 substrates might be underestimated after regular doses. We tested the dose linearity of an intravenous omeprazole microdose of 100 μg and compared it with a 20-mg dose in 4 healthy poor metabolizers (PMs) and 6 extensive metabolizers (EMs) of CYP2C19 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 (GMRs) of AUC 0-∞ 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 (AUC 0-4 GMR after 100 μg omeprazole, 4.61; 90% confidence interval [CI], 2.69-7.89; AUC 0-4 GMR after 20 mg omeprazole, 5.5; 90%CI, 1.07-1.46), whereas no clinically significant impact on PK in PMs was observed (GMR AUC 0-4 after 100 μg omeprazole, 1.29; 90%CI, 0.81-2.04; GMR AUC 0-4 after 20 mg omeprazole, 1.25; 90%CI, 1.07-1.46). Linear regression and Bland-Altman analyses revealed excellent agreement between AUC 0-∞ and AUC 0-4 of omeprazole (r 2 = 0.987; bias, 0.35%; 95%CI, −3.197% to 3.89%) and also the molar metabolic ratio, 5-OH omeprazole/omeprazole (r 2 = 0.987; bias, −3.939; 95%CI, −9.06% to −1.18%), suggesting that an abbreviated sampling protocol can be used for intravenous CYP2C19 phenotyping and drug interaction studies. In conclusion, the PK of intravenous omeprazole microdoses closely reflects the changes observed with regular omeprazole doses; however, to avoid autoinhibition of probe drugs, microdosing appears to be the favorable technique.

Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans

“…The amount of sodium bicarbonate administered with omeprazole seems to be important for absorption. Park and co-workers administered 10 mmol of sodium bicarbonate resulting in a relative bioavailability (F rel ) of 0.35 of the microdose [ 13 ]. Bioequivalence studies showed that uncoated omeprazole in combination with 48 mmol sodium bicarbonate was bioequivalent to an encapsulated formulation [ 21 ].…”

“…All participants had a known CYP2C19 genotype previously determined in a genotyping study where common cytochrome isozyme polymorphisms were examined. CYP2C19 genotyping was performed for CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), and for CYP2C19*17 (rs12248560) as previously described [ 13 ] and the presence of two wild type alleles was assumed if none of the tested polymorphisms was present.…”

“…Plasma concentrations of omeprazole and 5-OH-omeprazole after the 20 mg and 100 µg dose were analyzed with 2 different methods using high-performance and ultra-high performance liquid chromatography-tandem mass spectrometry (LC–MS/MS and UPLC-MS/MS) [ 13 ]. Calibration ranges were between 1–1000 ng/mL (LC–MS/MS) and 10–10,000 pg/mL (UPLC-MS/MS), respectively.…”

“…The LLOQ for the microdose were 10 pg/mL for both, omeprazole and 5-OH-omeprazole. Plasma concentrations could be quantified with within-batch and between-batch accuracies of 99–109% and precision of ≤ 13.2% [ 13 ].…”

“…Indeed, 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 ]. However, microdosed intravenous omeprazole has been shown to represent hepatic CYP2C19 activity recently [ 13 ].…”