Drug interaction evaluation of the novel phosphodiesterase type 5 inhibitor tunodafil (youkenafil): Effects of tunodafil on omeprazole pharmacokinetics based on CYP2C19 gene polymorphism, and effects of ritonavir on tunodafil pharmacokinetics

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-01-09 DOI:10.1016/j.ejps.2025.107010
Keli Wang , Juefang Ding , Minlu Cheng , Xianjing Li , Huan Zhou , Qinxin Song , Yuanxun Yang , Juan Li , Li Ding
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Abstract

Purpose

To evaluate the drug-drug interactions (DDI) of tunodafil (youkenafil), a novel phosphodiesterase type 5 inhibitor, its inhibitory effects on CYP450 enzymes in vitro and its clinical trials in combination with ritonavir or omeprazole were conducted.

Methods

The inhibitory effect of tunodafil on seven major CYP450 enzymes in human liver microsomes was investigated by probe substrate method. The effect of tunodafil on the pharmacokinetics of omeprazole (CYP2C19 substrate) in 40 healthy subjects, who received a single dose of 40 mg omeprazole in combination with tunodafil on the day 8 after taking 100 mg tunodafil daily for 7 days, was assessed based on CYP2C19 genotypes. The clinical DDI of ritonavir (potent CYP3A4 inhibitor) on tunodafil was studied in 28 healthy subjects who received a single dose of 50 mg tunodafil in combination with ritonavir on the day 6 after taking ritonavir twice a day for 5 days.

Results

Tunodafil showed moderate inhibition on CYP2C19 and CYP3A4/5 in vitro. When co-administration omeprazole with tunodafil, the AUC of omeprazole in the Extensive, Intermediate and Poor Metabolizers increased by 26 %, 37 % and 21 %, respectively. After co-administration tunodafil with ritonavir, ritonavir increased the AUC and Cmax of tunodafil in human by about 78- fold and 13-fold respectively.

Conclusions

Tunodafil slightly increased omeprazole exposure in the Extensive and Intermediate Metabolizers of CYP2C19, but had no significant effect on omeprazole exposure in the Poor Metabolizers. Ritonavir could strongly inhibit the metabolism of tunodafil, and the combination of tunodafil with ritonavir should be prohibited.

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新型磷酸二酯酶5型抑制剂妥诺他非(尤肯那非)的药物相互作用评价:基于CYP2C19基因多态性的妥诺他非对奥美拉唑药代动力学的影响,利托那韦对妥诺他非药代动力学的影响。
目的:评价新型磷酸二酯酶5型抑制剂妥诺非(youkenafil)的药物相互作用(DDI)、体外对CYP450酶的抑制作用及与利托那韦或奥美拉唑联合应用的临床试验。方法:采用探针底物法研究妥诺非对人肝微粒体中7种主要CYP450酶的抑制作用。以CYP2C19基因型为基础,观察40例健康受试者在连续7天每日服用100 mg妥诺非后,于第8天给予单剂量40 mg奥美拉唑联合妥诺非对奥美拉唑(CYP2C19底物)药代动力学的影响。研究了利托那韦(强效CYP3A4抑制剂)对妥那非的临床DDI。28名健康受试者在每日两次服用利托那韦5天后,于第6天接受单剂量50 mg妥那非与利托那韦联用。结果:妥诺非对体外培养的CYP2C19、CYP3A4/5有中等抑制作用。当奥美拉唑与妥诺非合用时,奥美拉唑在广泛代谢组、中等代谢组和不良代谢组的AUC分别增加26%、37%和21%。妥诺他非与利托那韦合用后,利托那韦使妥诺他非在人体内的AUC和Cmax分别提高约78倍和13倍。结论:妥诺非可轻微增加CYP2C19广泛代谢和中等代谢者的奥美拉唑暴露,但对低代谢者的奥美拉唑暴露无显著影响。利托那韦对妥诺非的代谢有强烈抑制作用,应禁止妥诺非与利托那韦合用。
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期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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