Cytochrome P450-Based Drug-Drug Interactions of Vonoprazan In Vitro and In Vivo

Abstract

Background: Vonoprazan fumarate is a potassium-competitive acid blocker that was developed as a novel acid-suppressing drug for multiple indications. As a potential alternative to proton-pump inhibitors, the determination of the drug-drug interactions is vital for further applications. Probe drug cocktails are a type of rapid, economical, and efficient approach for evaluating cytochrome P450 enzyme activities. Since vonoprazan is metabolized partly by cytochrome P450, cocktails were used to study CYP-based drugdrug interactions. Methods: This study was conducted both in vitro and in vivo. In the in vitro study of rat liver microsomes, ultra-performance liquid chromatography coupled to tandem mass spectrometry was utilized to assess the reversible inhibition of cytochrome P450 by vonoprazan by determining the concentration of probe drugs (phenacetin, bupropion, tolbutamide, dextromethorphan, midazolam, chlorzoxazone). The differences in the levels of probe drugs between the rat groups with or without vonoprazan administration were also tested in the rats. Results: In vitro analysis revealed that the IC 50 values of midazolam, tolbutamide, dextromethorphan, and bupropion in rat microsomes were 22.48, 18.34, 3.62, and 3.68 mM, respectively, while chlorzoxazone and phenacetin displayed no inhibition. In vivo analysis revealed that midazolam, bupropion, dextromethorphan, and tolbutamide showed significant (P < 0.05) differences in distinct pharmacokinetic parameters after vonoprazan administration, while those of chlorzoxazone and phenacetin were not significantly different. Conclusion: The in vitro and in vivo results indicated that vonoprazan can inhibit CYP3A4, CYP2C9, CYP2D6, and CYP2B6, suggesting that the coadministration of vonoprazan with cytochrome P450 substrates should be performed cautiously in clinical settings.

Impact of body size on first‐line Helicobacter pylori eradication success using vonoprazan and amoxicillin dual therapy

“…In contrast, because vonoprazan is mainly metabolized by CYP3A4, but not affected by CYP2C19 polymorphisms 15 ; thus, vonoprazan inhibits acid secretion in a stable manner with negligible difference among individuals. In addition, in vitro studies using rats have shown that combining drugs metabolized by CYP3A4 affects the concentration of each drug 16 . However, in the present study, there were no differences in the incidence of adverse events depending on whether or not other drugs metabolized by CYP3A4 were used; this indicates that the risk of drug interactions was low.…”

Effects of Concomitant Administration of Vonoprazan Fumarate on the Tacrolimus Blood Concentration in Kidney Transplant Recipients

“…To evaluate baseline kidney functions, eGFR (mL/min/1.73 m 2 ) was calculated using the appropriate equation shown in a previous report. 9) Tacrolimus C 0 (ng/mL) was monitored using a chemiluminescence immunoassay on the Architect-i1000 System (Abbott Japan, Tokyo, Japan).…”

The Universal Soldier: Enzymatic and Non-Enzymatic Antioxidant Functions of Serum Albumin

“…Some CYP450s operate in other tissues as well—for example, in cells of the cardiovascular system [ 3 ]. Currently, the efforts of many researchers are aimed at studying the role of CYP450 in drug–drug interactions and drug–disease interactions [ 16 , 17 , 18 ].…”