Background and objective: Malaria and tuberculosis remain endemic in tropical regions and most often coexist, increasing the burden of malaria mortality due to unintended interactions of the co-administered drugs employed in the management of the infections. Rifampicin (RIF) and amodiaquine (ADQ) are likely to be administered concurrently in the treatment of patients with tuberculosis and malaria. The metabolism of ADQ is mediated principally by CYP2C8, while RIF is a known inducer of this enzyme. This study, therefore, investigated the effect of RIF on the disposition of ADQ, a major partner drug in the first-line treatment against uncomplicated malaria in line with the World Health Organization recommendations. Methods:Sixteen healthy volunteers received oral 150 mg dose of RIF daily for 5 days with or without oral 600 mg single dose of ADQ on the fifth day (5 th dose) with a 4-week wash out period, in a crossover fashion. Blood samples were collected at predetermined time intervals of 0, 1, 2, 4, 6, 8, 12, 24, 36 and 48 h. Plasma samples were analyzed for ADQ and its major metabolite desethylamodiaquine using a validated RP-high-performance liquid chromatography. Pharmacokinetic parameters were obtained using appropriate software and subjected to appropriate statistical analysis. Results:Coadministration of ADQ and RIF resulted in significant decreases in the critical pharmacokinetic parameters of ADQ, such as area under the curve (AUC 0-∞ ) of about 66%, time to peak plasma concentration (Tmax) of about 10%, maximum plasma concentration of about 44%, and elimination half-life of about 55%, while the AUC 0-∞ and Tmax of the main metabolite desethylamodiaquine increased about 2-fold and 3-fold respectively during the coadministration of RIF with ADQ. The metabolic ratio increased significantly, from 1.55 to 2.68. The AUC 0-∞ and Tmax of the drug ADQ, as well as the maximum concentration of both the drug and its metabolite fell outside the point of estimates of the test/reference ratio of the geometric means of 80-125% of bioequivalence range. Conclusions:An interaction was established during coadministration of RIF and ADQ, confirming RIF as a strong inducer of CYP2C8 in vivo, which may lead to malaria therapeutic failure or adverse drug reactions with ADQ and contribute to the rate at which resistance to ADQ develops.