Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Abstract

As a novel acid-suppressing drug, vonoprazan shows the potential to replace traditional proton-pump inhibitors. With its widespread use, some adverse effects that require further study have emerged due to drug–drug interactions. Our study is the first experiment that evaluated the drug–drug interactions of eleven common cardiovascular drugs that inhibit vonoprazan metabolism in vitro and in vivo. Rat liver microsome incubation and molecular simulation docking were applied to explore the inhibition mechanism. Amlodipine and nifedipine showed inhibitory effects on vonoprazan metabolism in both rat and human liver microsomes in the first evaluation part in vitro. The inhibition mechanism analysis results demonstrated that amlodipine and nifedipine might inhibit the metabolism of vonoprazan by a mixed type of competitive and non-competitive inhibition. However, the pharmacokinetic data of the vonoprazan prototype revealed that amlodipine affected vonoprazan in vivo while nifedipine did not. Thus, more attention should be paid when amlodipine is prescribed with vonoprazan. Furthermore, the changes in its carboxylic acid metabolites MI hinted at a complex situation. Molecular simulation suggested the CYP2B6 enzyme may contribute more to this than CYP3A4, and further inhibitory experiments preliminarily verified this speculation. In conclusion, the use of vonoprazan with cardiovascular drugs, especially amlodipine, should receive particular attention in clinical prescriptions.

Inhibitory effect of Schisandrin on the pharmacokinetics of poziotinib in vivo and in vitro by UPLC‐MS/MS

“…Molecular docking simulations (Figure 7 ) were carried out to validate the compound‐target associations, using the methods previously described. 20 , 21 The BE less than −5.0 kcal/mol indicates a strong binding interaction between the small molecule and target protein. As shown in Figure 7a,b , SA and poziotinib bind closely with CYP3A4 in the same binding pocket, with BE of −6.8 kcal/mol and −9.2 kcal/mol, respectively.…”

“…Molecular docking simulations (Figure 7) were carried out to validate the compound‐target associations, using the methods previously described 20,21 . The BE less than −5.0 kcal/mol indicates a strong binding interaction between the small molecule and target protein.…”

Pharmacokinetics, Safety, and Tolerability of Vonoprazan‐ or Esomeprazole‐Based Bismuth‐Containing Quadruple Therapy: A Phase 1, Double‐Blind, Parallel‐Group Study in Adults with Helicobacter pylori Infection in China

“…6,8 Specifically, vonoprazan is metabolized oxidatively by multiple liver CYP450 enzymes (eg, CYP3A4, CYP2B6, and CYP2D6) and nonoxidatively by sulfotransferase; however, CYP3A4 is the primary metabolic pathway. 9,10 Interference with the metabolism of vonoprazan by clarithromycin, a potent inhibitor of CYP3A4, provides corroborative evidence that the major metabolic disposition pathway of vonoprazan occurs via CYP3A4. 11 Bismuth absorption and elimination have been studied by analyzing its PK in human plasma and urine, which showed that <1% of the administered dose is absorbed, and renal excretion is the primary route of bismuth elimination.…”

“…Moreover, vonoprazan is not primarily metabolized by CYP2C19; therefore, CYP2C19 polymorphism has limited influence on the acid‐inhibitory effect of vonoprazan 6,8 . Specifically, vonoprazan is metabolized oxidatively by multiple liver CYP450 enzymes (eg, CYP3A4, CYP2B6, and CYP2D6) and nonoxidatively by sulfotransferase; however, CYP3A4 is the primary metabolic pathway 9,10 . Interference with the metabolism of vonoprazan by clarithromycin, a potent inhibitor of CYP3A4, provides corroborative evidence that the major metabolic disposition pathway of vonoprazan occurs via CYP3A4 11 …”

Impact of Cytochrome P450 Enzymes on the Phase I Metabolism of Drugs

“…M-III derives from the oxidation of the secondary amino group to the nitron form, whereas M-IV-Sul derives from the N-sulfation of the secondary amino group, following hydroxylation of the fluorophenyl ring [111]. Recent molecular modelling studies suggested that CYP2B6 may contribute to vonoprazan metabolism more than CYP3A4 [112]. Moreover, vonoprazan inhibits CYP2B6 and CYP3A4/5 [113].…”