RT Journal Article SR Electronic T1 Inhibitory effects of selected antituberculosis drugs on common human hepatic cytochrome P450 and UDP-glucuronosyltransferase enzymes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.117.076034 DO 10.1124/dmd.117.076034 A1 Lei Cao A1 David J. Greenblatt A1 Awewura Kwara YR 2017 UL http://dmd.aspetjournals.org/content/early/2017/06/26/dmd.117.076034.abstract AB The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of 5 first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for 6 common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs. Pyrazinamide, ethambutol, rifabutin and bedaquiline were also studied for their inhibitory effects on 8 of the most common human CYP enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). Rifabutin inhibited multiple CYPs to varying degrees in vitro, but with all IC50 values exceeding 25 μM. Rifabutin and rifampicin also inhibited several human UGTs including UGT1A4. The Ki value for rifabutin on human hepatic UGT1A4 was 2 μM. Finally, the 6 anti-TB drugs produced minimal inhibition of acetaminophen glucuronidation in vitro. Overall, the findings do not raise major concerns regarding metabolic inhibition of human hepatic CYPs and UGTs by the tested anti-TB drugs.