In Vitro and In Vivo Rat Model Assessments of the Effects of Vonoprazan on the Pharmacokinetics of Venlafaxine

Abstract

Purpose: The purpose of the present study was to investigate the effects of vonoprazan on the pharmacokinetics of venlafaxine in vitro and in vivo.

Methods: The mechanism underlying the inhibitory effect of vonoprazan on venlafaxine was investigated using rat liver microsomes. In vitro, the inhibition was evaluated by determining the production of O-desmethylvenlafaxine. Eighteen male Sprague-Dawley rats were randomly divided into three groups: control group, vonoprazan (5 mg/kg) group, and vonoprazan (20 mg/kg) group. A single dose of 20 mg/kg venlafaxine was administrated to rats orally without or with vonoprazan. Plasma was prepared from blood samples collected via the tail vein at different time points and concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine, were determined by ultra-performance liquid chromatography-tandem mass spectrometry.

Results: We observed that vonoprazan could significantly decrease the amount of O-desmethylvenlafaxine (IC₅₀ = 5.544 μM). Vonoprazan inhibited the metabolism of venlafaxine by a mixed inhibition, combining competitive and non-competitive inhibitory mechanisms. Compared with that in the control group (without vonoprazan), the pharmacokinetic parameters of venlafaxine and its metabolite, O-desmethylvenlafaxine, were significantly increased in both 5 and 20 mg/kg vonoprazan groups, with an increase in MR_{O-desmethylvenlafaxine}.

Conclusion: Vonoprazan significantly alters the pharmacokinetics of venlafaxine in vitro and in vivo. Further investigations should be conducted to check these effects in humans. Therapeutic drug monitoring of venlafaxine in individuals undergoing venlafaxine maintenance therapy is recommended when vonoprazan is used concomitantly.

Keywords: gastroduodenal ulcer; gastroesophageal reflux disease; proton pump inhibitors; vonoprazan fumarate.

Figure 1

Venlafaxine metabolism to O-desmethylvenlafaxine, N-desmethylvenlafaxine, and N, O-didesmethylvenlafaxine.

Figure 2

Typical MRM chromatograms of venlafaxine, O-desmethylvenlafaxine and diazepam (IS).

Figure 3

(A) Substrate saturation plots, from product formation data, for venlafaxine (1–200 µM) in RLMs. (B) Effect of the vonoprazan on venlafaxine metabolism in RLMs (vonoprazan 0.1–100 µM).

Figure 4

Lineweaver–Burk plots for vonoprazan inhibition of venlafaxine in rat livers microsomes. Data shown are the mean ± standard deviation of triplicate experiment. (A) Lineweaver–Burk plots for vonoprazan (0, 1.25, 2.5, 5, 10 μM) inhibition of venlafaxine (2, 4, 6, 8 μΜ) in rat livers microsomes. (B) Slope of Primary Plot. (C) Intercept of Primary Plot.

Figure 5

Mean plasma concentration–time profiles of venlafaxine (A) and O-desmethylvenlafaxine (B) after an oral administration of venlafaxine (20 mg/kg) to rats in the presence and absence of vonoprazan (5 and 20 mg/kg) (mean ± S.D., n=6); (1) Low-dose group was pretreat with vonoprazan (5 mg/kg, oral); (2) High-dose group was pretreat with vonoprazan (20 mg/kg, oral); (3) Control group was administered by venlafaxine (20 mg/kg, oral).