Rifabutin reduces systemic exposure of an antimalarial drug 97/78 upon co-administration in rats:an in-vivo & in-vitro analysis  

作　　者：Yeshwant Singh Mahendra Kumar Hidau Shio Kumar Singh 

机构地区：[1]Pharmacokinetics & Metabolism Division,CSIR-Central Drug Research Institute [2]Academy of Scientific and Innovative Research

出　　处：《Asian Pacific Journal of Tropical Medicine》2015年第8期620-625,共6页亚太热带医药杂志（英文版）

基　　金：the Council for Scientific and Industrial Research (CSIR),India,for providing research fellowships

摘　　要：Objective: To determine the potential drug-drug interactions between anti-malarial candidate 97/78 and anti-tubercular drug rifabutin in-vivo in rats followed by in-vitro investigation of the underlying mechanisms of drug interaction. Methods: Single oral dose study was conducted in male and female rats at 40 mg/kg and 70 mg/kg for 97/78 and rifabutin respectively. Results: It was reported that rifabutin co-administration altered pharmacokinetics of 97/63(active metabolite of 97/78). A significant decrease was reported in the systemic exposure of 97/63 by a factor of 3-4. The AUC0-last values were(4.03 ± 0.60) and(5.44 ± 1.15) μg·h·m L-1 upon 97/78 administration alone, while the values were decreased to(1.13 ± 0.10) and(1.23 ± 1.13) μg·h·m L-1 upon rifabutin co-administration in male and female rats respectively. Statistically significant differences were also reported in Cmax and Tmax values upon rifabutin co-administration. In-vitro drug metabolism study in rat liver microsomes has shown that the metabolism of 97/63 was increased by 10%-12% upon rifabutin co-incubation. The extent of plasma protein binding of 97/63 was found to be decreased from 54%-55% to 6%-8% upon rifabutin addition. Conclusions: It was concluded that rifabutin co-administration altered PK parameters of 97/63 in SD rats. However, no intersex influences were reported in the interaction pattern. The results obtained in the in-vivo study were well correlated with the invitro findings and can further be applied to explore other aspects of potential drug interactions between these two drugs.Objective: To determine the potential drug-drug interactions between anti-malarial candidate 97/78 and anti-tubercular drug rifabutin in-vivo in rats followed by in-vitro investigation of the underlying mechanisms of drug interaction. Methods: Single oral dose study was conducted in male and female rats at 40 mg/kg and 70 mg/kg for 97/78 and rifabutin respectively. Results: It was reported that rifabutin co-administration altered pharmacokinetics of 97/63(active metabolite of 97/78). A significant decrease was reported in the systemic exposure of 97/63 by a factor of 3-4. The AUC0-last values were(4.03 ± 0.60) and(5.44 ± 1.15) μg·h·m L-1 upon 97/78 administration alone, while the values were decreased to(1.13 ± 0.10) and(1.23 ± 1.13) μg·h·m L-1 upon rifabutin co-administration in male and female rats respectively. Statistically significant differences were also reported in Cmax and Tmax values upon rifabutin co-administration. In-vitro drug metabolism study in rat liver microsomes has shown that the metabolism of 97/63 was increased by 10%-12% upon rifabutin co-incubation. The extent of plasma protein binding of 97/63 was found to be decreased from 54%-55% to 6%-8% upon rifabutin addition. Conclusions: It was concluded that rifabutin co-administration altered PK parameters of 97/63 in SD rats. However, no intersex influences were reported in the interaction pattern. The results obtained in the in-vivo study were well correlated with the invitro findings and can further be applied to explore other aspects of potential drug interactions between these two drugs.

关 键 词：Accumulation Relative BIOAVAILABILITY SEX effect PHARMACOKINETICS 

分 类 号：R965[医药卫生—药理学]