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

ObjectiveTo 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.MethodsSingle oral dose study was conducted in male and female rats at 40 mg/kg and 70 mg/kg for 97/78 and rifabutin respectively.ResultsIt 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.ConclusionsIt 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.