Asunaprevir,daclatasvir,beclabuvir是直接作用的抗病毒药物,用于治疗感染基因型1b的丙型肝炎患者。本文综述了这些药物的生物转化和处置与治疗安全性和有效性的关系。CYP3A4和3A5催化药物的氧化生物转化,而P-糖蛋白介导它们从组织中流出。Asunaprevir也是内流转运蛋白OATP1B1和OATP2B1以及外流转运蛋白MRP2的底物,而beclabuvir也是外流转运蛋白BCRP的底物。肝病降低介导药物代谢和处置的CYPs和转运蛋白的表达。血清asunaprevir浓度,但不是那些daclatasvir或beclabuvir,在严重肝病患者中增加,这可能会产生毒性。CYPs和转运蛋白的药物基因组变异也有可能破坏asunaprevir的治疗,daclatasvir和beclabuvir;一些变体在某些种族群体中更为普遍。药代动力学药物-药物相互作用,尤其是asunaprevir的地方,daclatasvir,Beclabuvir是受害者的药物,由共同施用的利福平介导,酮康唑和利托那韦,并且可归因于CYP和转运蛋白的抑制和/或诱导。相反,也有证据表明asunaprevir,daclatasvir和beclabuvir是与瑞舒伐他汀和右美沙芬共同给药的药物相互作用的肇事者.一起,肝病,药物基因组变异和药物-药物相互作用可能会破坏。
Asunaprevir,
daclatasvir, and beclabuvir are direct-acting antiviral agents used in the treatment of patients infected with hepatitis C genotype 1b. This article reviews the biotransformation and disposition of these drugs in relation to the safety and efficacy of therapy. CYP3A4 and 3A5 catalyze the oxidative biotransformation of the drugs, while P-glycoprotein mediates their efflux from tissues. Asunaprevir is also a substrate for the influx transporters OATP1B1 and OATP2B1 and the efflux transporter MRP2, while beclabuvir is also a substrate for the efflux transporter BCRP. Liver disease decreases the expression of CYPs and transporters that mediate drug metabolism and disposition. Serum asunaprevir concentrations, but not those of
daclatasvir or beclabuvir, are increased in patients with severe liver disease, which may produce toxicity. Pharmacogenomic variation in CYPs and transporters also has the potential to disrupt therapy with asunaprevir, daclatasvir and beclabuvir; some variants are more prevalent in certain racial groups. Pharmacokinetic drug-drug interactions, especially where asunaprevir,
daclatasvir, and beclabuvir are victim drugs, are mediated by coadministered rifampicin, ketoconazole and ritonavir, and are attributable to inhibition and/or induction of CYPs and transporters. Conversely, there is also evidence that asunaprevir,
daclatasvir and beclabuvir are perpetrators of drug interactions with coadministered rosuvastatin and dextromethorphan. Together, liver disease, pharmacogenomic variation and drug-drug interactions may disrupt therapy with asunaprevir,
daclatasvir and beclabuvir due to the impaired function of important CYPs and transporters.