Effect of High-Dose Esomeprazole on CYP1A2, CYP2C19, and CYP3A4 Activities in Humans: Evidence for Substantial and Long-lasting Inhibition of CYP2C19

Autor: Aleksi Tornio, Tuija Tapaninen, Janne T. Backman, Terhi Launiainen, Nina Isoherranen, Taavi J. K. Kaartinen, Mikko Niemi
Přispěvatelé: University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, University of Helsinki, HUSLAB, University of Helsinki, Helsinki University Hospital Area, INDIVIDRUG - Individualized Drug Therapy, HUSLAB, Helsinki University Hospital Area, Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Research Programs Unit, Medicum, Janne Backman / Principal Investigator, Clinicum
Rok vydání: 2020
Předmět:
Male
Pharmacogenomic Variants
Administration
Oral
BREATH TEST
Pharmacology
030226 pharmacology & pharmacy
STEREOSELECTIVE PHARMACOKINETICS
Esomeprazole
chemistry.chemical_compound
0302 clinical medicine
Cytochrome P-450 CYP3A
Pharmacology (medical)
Pantoprazole
Omeprazole
DRUG-INTERACTION
Paraxanthine
Cross-Over Studies
OMEPRAZOLE
Cytochrome P-450 CYP1A2 Inducers
Healthy Volunteers
3. Good health
317 Pharmacy
030220 oncology & carcinogenesis
Female
Caffeine
medicine.drug
PROTON PUMP INHIBITOR
Midazolam
METABOLISM
Models
Biological
03 medical and health sciences
Pharmacokinetics
Cytochrome P-450 CYP1A2
medicine
Humans
PH PROFILES
CYTOCHROME-P450
IN-VITRO
Drug interaction
Cytochrome P-450 CYP2C19
chemistry
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP3A Inhibitors
3111 Biomedicine
DEPENDENT INHIBITOR
Zdroj: Clinical pharmacology and therapeutics. 108(6)
ISSN: 1532-6535
Popis: In vitro, esomeprazole is a time-dependent inhibitor of CYP2C19. Additionally, racemic omeprazole induces CYP1A2 and omeprazole and its metabolites inhibit CYP3A4 in vitro. In this 5-phase study, 10 healthy volunteers ingested 20 mg pantoprazole, 0.5 mg midazolam, and 50 mg caffeine as respective index substrates for CYP2C19, 3A4, and 1A2 before and 1, 25, 49 (pantoprazole only), and 73 hours after an 8-day pretreatment with 80 mg esomeprazole twice daily. The area under the plasma concentration-time curve (AUC) of R-pantoprazole increased 4.92-fold (90% confidence interval (CI) 3.55-6.82), 2.31-fold (90% CI 1.85-2.88), and 1.33-fold (90% CI 1.06-1.68) at the 1-hour, 25-hour, and 73-hour phases, respectively, consistent with a substantial and persistent inhibition of CYP2C19. The AUC of midazolam increased up to 1.44-fold (90% CI 1.22-1.72) and the paraxanthine/caffeine metabolic ratio up to 1.19-fold (90% CI 1.04-1.36), when the index substrates were taken 1 hour after esomeprazole. Based on the recovery of R-pantoprazole oral clearance, the turnover half- life of CYP2C19 was estimated to average 53 hours. Pharmacokinetic simulation based on the observed concentrations of esomeprazole and its metabolites as well as their published CYP2C19 inhibitory constants was well in line with the observed changes in R-pantoprazole pharmacokinetics during the course of the study. Extrapolations assuming linear pharmacokinetics of esomeprazole suggested weak to moderate inhibition at 20 and 40 mg twice daily dosing. In conclusion, high-dose esomeprazole can cause strong inhibition of CYP2C19, but only weakly inhibits CYP3A4 and leads to minor induction of CYP1A2. The enzymatic activity of CYP2C19 recovers gradually in similar to 3-4 days after discontinuation of esomeprazole treatment.
Databáze: OpenAIRE
Externí odkaz: