AUTHOR=Wang Yiran , Wang Changxiong , Wang Shuanghu , Zhou Quan , Dai Dapeng , Shi Jihua , Xu Xue , Luo Qingfeng 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00053

DOI=10.3389/fphar.2020.00053

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>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 drug-drug interactions.</p></sec><sec><title>Methods</title><p>This study was conducted both <italic>in vitro</italic> and <italic>in vivo</italic>. In the <italic>in vitro</italic> 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.</p></sec><sec><title>Results</title><p><italic>In vitro</italic> analysis revealed that the IC<sub>50</sub> values of midazolam, tolbutamide, dextromethorphan, and bupropion in rat microsomes were 22.48, 18.34, 3.62, and 3.68 μM, respectively, while chlorzoxazone and phenacetin displayed no inhibition. <italic>In vivo</italic> analysis revealed that midazolam, bupropion, dextromethorphan, and tolbutamide showed significant (<italic>P</italic> &lt; 0.05) differences in distinct pharmacokinetic parameters after vonoprazan administration, while those of chlorzoxazone and phenacetin were not significantly different.</p></sec><sec><title>Conclusion</title><p>The <italic>in vitro</italic> and <italic>in vivo</italic> 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.</p></sec>