Evaluation of a pantoprazole and 4-desmethylpantoprazole-sulfate metabolic ratio as a novel CYP2C19 phenotyping method

Aims: CYP2C19 is one of the most important pharmacogenes, and its activity is highly variable due to factors such as genetics or drug-drug interactions. Due to the lack of an appropriate endogenous CYP2C19 biomarker, surrogate methods to assess its activity are warranted. The aim of this work was to validate pantoprazole as a CYP2C19 phenotyping drug.

Methods: We performed a single-dose pharmacokinetic study with 20 healthy participants in a randomized cross-over design. Participants received 10 mg omeprazole and 20 mg pantoprazole on two different study days with a washout phase of one week. Blood sampling was performed at 14 time points spanning 8 h after drug administration. Drug and metabolite plasma concentrations were assessed by LC-MS/MS. Metabolic ratios (MR) of metabolite/substrate were formed using the area under the curve from 0 to 8 h (AUC_0-8h) and single plasma concentrations.

Results: We demonstrate very strong correlations (Spearman ρ = 0.84) of AUC_0-8h MR 4-desmethylpantoprazole-sulfate/pantoprazole to the validated CYP2C19 probe AUC_0-8h MR 5-hydroxyomeprazole/omeprazole (Spearman ρ = 0.84). Single time point pantoprazole MRs measured in plasma between 4 and 8 h after pantoprazole administration were sufficient for accurate CYP2C19 phenotyping by demonstrating significant and robust correlations to the AUC_0-8h MR 5-hydroxyomeprazole/omeprazole with Spearman ρ ≥ 0.8.

Conclusions: In contrast to omeprazole, pharmacokinetics of pantoprazole are described to be stable during repeated dosing, which may allow phenotyping of CYP2C19 with patients using pantoprazole MRs in situations where pantoprazole is part of the prescribed medication.

CYP2C19; cytochrome P450; drug–drug interactions; personalized medicine; pharmacogenetics; pharmacokinetics.