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
Keli Wang , Juefang Ding , Minlu Cheng , Xianjing Li , Huan Zhou , Qinxin Song , Yuanxun Yang , Juan Li , Li Ding
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引用次数: 0
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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