Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers

Abstract

Influence of fluconazole on the pharmacokinetics of omeprazole was evaluated by single oral administration of omeprazole capsule 20 mg (control group), or single oral administration of fluconazole capsule, 100 mg, and omeprazole, 20 mg, after 4 days of daily oral administration of fluconazole, 100 mg (treated group), to 18 healthy male volunteers. Omeprazole is extensively metabolized in the liver through 5-hydroxylation and sulfoxidation reactions catalyzed predominantly by CYP2C19 and CYP3A4, respectively. Fluconazole is a potent competitive inhibitor of CYP2C19 and a weak inhibitor of CYP3A4. In treated group, the area under the plasma concentration-time curve of omeprazole from time zero to time infinity (AUC) was significantly greater (3090 vs 491 ng h/ml), terminal half-life of omeprazole was significantly longer (2.59 vs 0.85 h), and peak plasma concentration of omeprazole (C(max)) was significantly higher (746 vs 311 ng/ml) than that in control group. The greater AUC and higher C(max) in treated group could be due to inhibition of omeprazole metabolism by fluconazole.

Fluconazole but not the CYP3A4 inhibitor, itraconazole, increases zafirlukast plasma concentrations

“…In humans, fluconazole has increased the CYP2C19 substrate diazepam AUC 2.5-fold and that of omeprazole 6.3-fold [37,38]. However, CYP2C19 has catalyzed the formation of only some minor zafirlukast metabolites in vitro [9].…”

Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients and Implications for Patient Care

“…The AUC of omeprazole increased 6.3-fold in healthy volunteers who received fluconazole; this interaction may have led to an increased effect of omeprazole [117].…”

“…Reports of interactions of fluconazole with carbamazepine in patients [101][102][103] Warfarin: prothrombin times [71,106] and INR values [107] Monitor carefully: prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants [71] Fluconazole increased exposure to simvastatin [109,110], atorvastatin [111], and fluvastatin; fluvastatin Cmax 44% (P <0.05), AUC 84% (P <0.01), t 80% (P <0.01) [112] Fluconazole increased exposure to omeprazole: AUC 6.3-fold [117] Itraconazole Phenytoin decreased exposure to itraconazole: AUC >90%, t from 22.3 to 3.8 hours [104] Itraconazole increased AUC of phenytoin by 10.3% [104] Possibility of an interaction with carbamazepine [9] Itraconazole significantly increased exposure (Cmax, AUC, and t ) to lovastatin [113], simvastatin [114], atorvastatin [115,116], and cerivastatin [115] Contraindicated: Coadministration of itraconazole with lovastatin or simvastatin [9] PPIs and H2 antagonists significantly reduced itraconazole absorption [1,87,118] Voriconazole Phenytoin decreased exposure to voriconazole: Cmax 50% , AUC 70% Voriconazole increased plasma concentrations of phenytoin:…”

Arzneimittelinteraktionen

“…In ⊡ Tabelle 2 sind die wichtigsten Interaktionen von Omeprazol und die beteiligten CYP-Isoformen zusammengefasst [21,22,24,38].…”