Rifabutin reduces systemic exposure of an antimalarial drug 97/78 upon co-administration in rats: An in-vivo & in-vitro analysis
10.1016/j.apjtm.2015.07.013
- Author:
Yeshwant SINGH
1
;
Mahendra Kumar HIDAU
1
;
Shio Kumar SINGH
1
;
Mahendra Kumar HIDAU
2
Author Information
1. Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute
2. Academy of Scientific and Innovative Research
- Publication Type:Journal Article
- Keywords:
Accumulation;
Pharmacokinetics;
Relative bioavailability;
Sex effect
- From:
Asian Pacific Journal of Tropical Medicine
2015;8(8):630-635
- CountryChina
- Language:Chinese
-
Abstract:
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 mL-1 upon 97/78 administration alone, while the values were decreased to (1.13 ± 0.10) and (1.23 ± 1.13) μg h mL-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 in-vitro findings and can further be applied to explore other aspects of potential drug interactions between these two drugs.
