Characterization of plasma vonoprazan and CYP3A activity using its endogenous marker and genetic variants in patients with digestive system disorders

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY Drug Metabolism and Pharmacokinetics Pub Date : 2024-10-01 DOI:10.1016/j.dmpk.2024.101027

Kenta Sakaguchi , Takafumi Naito , Kohei Hoshikawa , Yukari Miyadera , Hironari Tanaka , Emi Nakatsugawa , Takahisa Furuta , Ken Sugimoto , Junichi Kawakami

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Abstract

Factors that determine clinical responses to vonoprazan remain unknown. This study aimed to characterize plasma vonoprazan and CYP3A activity using its endogenous marker and genetic variants in patients with digestive system disorders. Fifty-three patients who were receiving vonoprazan for at least 3 days were enrolled. Blood samples for determination of plasma vonoprazan and its metabolite (ODA-VP) were obtained. Plasma 4β-hydroxycholesterol (4β-OHC), CYP3A5 and ABCB1 genotypes, and plasma gastrin were determined. CYP3A recognition for vonoprazan was evaluated using recombinant CYP3A proteins. Plasma vonoprazan levels exhibited a large interindividual variation. The absolute plasma concentration of vonoprazan was correlated with its dose-normalized value, and had a positive correlation with the inverse value of its metabolic ratio. A negative correlation was observed between plasma vonoprazan and 4β-OHC levels. The metabolic ratio of vonoprazan was positively correlated with the plasma 4β-OHC level. Genetic variants of CYP3A5 and ABCB1 were not associated with the plasma concentration of vonoprazan and its metabolic ratio. Possible saturated metabolism of vonoprazan to its major metabolite was observed at a therapeutic dose. Although the CYP3A5 genotype did not alter plasma vonoprazan, CYP3A activity based on plasma 4β-OHC partially explained the variation in plasma vonoprazan in patients with digestive system disorders.

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利用消化系统疾病患者的内源性标记物和遗传变异分析血浆中伏诺派赞和 CYP3A 活性的特征

决定对伏诺普拉赞临床反应的因素尚不清楚。本研究旨在利用消化系统疾病患者的内源性标记物和基因变异来描述血浆中伏诺派赞和 CYP3A 活性的特征。53 名患者接受了至少 3 天的 Vonoprazan 治疗。采集血样测定血浆中伏诺派赞及其代谢物（ODA-VP）。还测定了血浆 4β- 羟基胆固醇（4β-OHC）、CYP3A5 和 ABCB1 基因型以及血浆胃泌素。使用重组 CYP3A 蛋白评估了 CYP3A 对 vonoprazan 的识别能力。血浆中的沃诺普拉赞水平存在较大的个体差异。血浆中 vonoprazan 的绝对浓度与其剂量归一化值相关，与其代谢比值的倒数呈正相关。血浆中的沃诺普拉赞与 4β-OHC 水平呈负相关。沃诺普拉赞的代谢比值与血浆中 4β-OHC 的水平呈正相关。CYP3A5和ABCB1的基因变异与血浆中vonoprazan的浓度及其代谢比率无关。在治疗剂量下，vonoprazan可能饱和代谢为其主要代谢物。虽然 CYP3A5 基因型不会改变血浆中的沃诺普拉赞，但基于血浆 4β-OHC 的 CYP3A 活性可部分解释消化系统疾病患者血浆中沃诺普拉赞的变化。

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来源期刊

Drug Metabolism and Pharmacokinetics 医学-药学

CiteScore

4.80

自引率

9.50%

发文量

审稿时长

69 days

期刊介绍： DMPK publishes original and innovative scientific papers that address topics broadly related to xenobiotics. The term xenobiotic includes medicinal as well as environmental and agricultural chemicals and macromolecules. The journal is organized into sections as follows: - Drug metabolism / Biotransformation - Pharmacokinetics and pharmacodynamics - Toxicokinetics and toxicodynamics - Drug-drug interaction / Drug-food interaction - Mechanism of drug absorption and disposition (including transporter) - Drug delivery system - Clinical pharmacy and pharmacology - Analytical method - Factors affecting drug metabolism and transport - Expression of genes for drug-metabolizing enzymes and transporters - Pharmacogenetics and pharmacogenomics - Pharmacoepidemiology.