EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2025
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IF 4.7
Keli Wang,Juefang Ding,Minlu Cheng,Xianjing Li,Huan Zhou,Qinxin Song,Yuanxun Yang,Juan Li,Li Ding
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 C max 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.
研究领域:
药理学
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临床药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Shuaishuai Chen,Weiyu Guo,Huan Liu,Jiang Zheng,Dingyan Lu,Jia Sun,Chun Li,Chunhua Liu,Yonglin Wang,Yong Huang,Wen Liu,Yongjun Li,Ting Liu
Psoralen and isopsoralen are the major components responsible for Psoraleae Fructus-induced hepatotoxicity. This study explored the role of metabolic activation by cytochrome P450 (CYP) enzymes in psoralen- and isopsoralen-induced cytotoxicity and its potential mechanisms. Inhibitors of CYP1A2 , 2C9, 2C19, 2D6, 2E1, and 3A4 were used to screen specific CYP enzymes responsible for the metabolic activation of psoralen and isopsoralen in mouse primary hepatocytes, which was verified using the corresponding transfected cell lines. Network toxicology and transcriptome analyses were performed to explore the mechanisms underlying toxicity. Psoralen and isopsoralen decreased the viability of mouse primary hepatocytes, whereas the inhibition of CYP2C9 , 2C19, 2D6, and 2E1 significantly increased their viability. Psoralen-induced cytotoxicity was significantly enhanced by the overexpression of CYP2C19 in Chinese hamster ovary cells, whereas the overexpression of the above CYP enzymes did not affect the cytotoxicity of isopsoralen. Psoralen- and isopsoralen-induced cytotoxic effects were associated with putative core targets (i.e., Fn1 , Thbs1 , and Tlr2) and multiple signaling pathways (e.g., PI3K-Akt, MAPK , and TNF pathways). Our results demonstrate that the metabolic activation of psoralen and isopsoralen is mediated by CYP enzymes, thereby regulating multiple core targets and signaling pathways and resulting in cytotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
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2021
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IF 3.534
Zifei Qin,Peile Wang,Shuyi Duan,Xiaoying Wan,Han Xing,Jing Yang,Xiaojian Zhang,Zhihong Yao,Xinsheng Yao
Isobavachalcone, a naturally occurring chalcone in Psoralea corylifolia , posses many biological properties including anticancer, antiplatelet, and antifungal. However, its glucuronidation, glucuronides excretion, and drug-drug interaction (DDI) involving in human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) enzymes, and efflux transporters (BCRP and MRPs) remains unclear so far. After incubation, three glucuronides were produced by HLM and HIM with total intrinsic clearance ( CL int ) of 236.71 and 323.40 μL/min/mg, respectively. Reaction phenotyping proved UGT1A1, 1A3, 1A7, 1A8, and 1A9 played important roles in glucuronidation with total CL int values of 62.69–143.00 μL/min/mg. Activity correlation analysis indicated UGT1A1 and UGT1A3 participated more in the glucuronidation. In addition, the glucuronidation showed marked species differences, and rabbits and dogs were probably appropriate model animals to investigate the in vivo glucuronidation. Furthermore, BCRP , MRP1, and MRP4 transporters were identified as the most important contributors to glucuronides excretion in HeLa1A1 cells based on gene silencing method. Moreover, isobavachalcone demonstrated broad-spectrum inhibitory effects against CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6 , CYP2E1 , UGT1A1, UGT1A9, UGT2B7 with IC 50 values of 1.08–9.78 μM. Except CYP2B6 and CYP2D6, the calculated [I]/ K i values for other enzymes were all greater than 0.1, indicating the inhibition of systemic metabolism or elimination for these enzyme substrates seems likely. Taken together, we summarized metabolic fates of isobavachalcone including glucuronidation and efflux transport as well as inhibitory effects involving in human CYP and UGT enzymes.
研究领域:
药理学
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生物化学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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