Curcumin Enhances the Systemic Exposure of Isoniazid in Rats: Role of NAT2 in the Liver and Intestine

Abstract

Background and Objective: N-acetyltransferase 2 (NAT2) is the main enzyme that responsible for isoniazid (INH) metabolism, the expression and function of NAT2 play important roles in the pathogenesis of INH-induced hepatotoxicity. Concerning the potential inhibitory effect of curcumin on NAT2, it is of great importance to know the effect of curcumin on INH metabolism and evaluate enzyme-mediated drug-drug interaction. Materials and Methods: Male Wistar rats were orally administered with INH (60 mg kg-1) alone or in combination with curcumin (100 mg kg-1). The serum concentration and tissue distribution of INH and its metabolite acetylisoniazid (AcINH) were determined using HPLC-MS/MS, the protein expression and function of NAT2 in the liver and small intestine were evaluated further and molecular docking technique was also applied to explore the interaction between curcumin and NAT2. Results: Curcumin pretreatment significantly elevated the serum concentration and tissue distribution of INH accompanied with marked reduction of AcINH, the parameter AUC0→t, t1/2 and Cmax in curcumin pretreated rats were all significantly increased, while CL/F was markedly reduced. NAT2 activity in the liver and small intestine were significantly inhibited by curcumin pretreatment. Molecular docking study showed that curcumin could locate at the hydrophobic pocket and form a strong binding to NAT2. Conclusion: Results from this study indicate that curcumin could inhibit NAT2 activity and further affect the pharmacokinetics of INH. This study may provide a cue for reducing INH-induced hepatotoxicity and improving INH potency by curcumin co-administration.