Cao Lei, Greenblatt David J, Kwara Awewura
Graduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences (L.C., D.J.G.) and Department of Integrative Physiology and Pathobiology (D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island (A.K.); and The Miriam Hospital, Providence, Rhode Island (A.K.).
Graduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences (L.C., D.J.G.) and Department of Integrative Physiology and Pathobiology (D.J.G.), Tufts University School of Medicine, Boston, Massachusetts; Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island (A.K.); and The Miriam Hospital, Providence, Rhode Island (A.K.)
Drug Metab Dispos. 2017 Sep;45(9):1035-1043. doi: 10.1124/dmd.117.076034. Epub 2017 Jun 29.
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 five first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for six 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 eight 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 IC values exceeding 25 µM. Rifabutin and rifampicin also inhibited several human UGTs including UGT1A4. The K value for rifabutin on human hepatic UGT1A4 was 2 μM. Finally, the six 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.
结核病与诸如艾滋病毒等疾病的合并症需要使用多种药物进行长期治疗。尽管有大量关于利福平及异烟肼对人细胞色素P450（CYPs）影响的体外和体内信息，但关于其他抗结核药物对人CYPs和尿苷二磷酸葡萄糖醛酸转移酶（UGTs）抑制作用的已发表数据有限。使用人肝微粒体（HLMs）在体外评估了五种一线抗结核药物（异烟肼、利福平、吡嗪酰胺、乙胺丁醇和利福布汀）以及新批准的贝达喹啉对六种常见人肝UGT酶（UGT1A1、1A4、1A6、1A9、2B7和2B15）的抑制作用。还研究了吡嗪酰胺、乙胺丁醇、利福布汀和贝达喹啉对八种最常见人CYP酶（CYP1A2、2B6、2C8、2C9、2C19、2D6、2E1和3A）的抑制作用。利福布汀在体外不同程度地抑制多种CYPs，但所有半数抑制浓度（IC）值均超过25μM。利福布汀和利福平还抑制包括UGT1A4在内的几种人UGTs。利福布汀对人肝UGT1A4的解离常数（K）值为2μM。最后，这六种抗结核药物在体外对乙酰氨基酚葡萄糖醛酸化的抑制作用极小。总体而言，这些研究结果并未引发关于受试抗结核药物对人肝CYPs和UGTs代谢抑制的重大担忧。
