Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity
文献类型：期刊论文
| 作者 | Ma, Lei-lei1,3,4; Wu, Zhi-tao1; Wang, Le1; Zhang, Xue-feng2; Wang, Jing2; Chen, Chen5; Ni, Xuan1; Lin, Yun-fei1; Cao, Yi-yi3,4; Luan, Yang3,4 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2016-03 |
| 卷号 | 37期号:3页码:415-424 |
| 关键词 | leflunomide hepatotoxicity CYPs teriflunomide aminobenzotriazole proadifen NTCP cholestasis |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2015.157 |
| 文献子类 | Article |
| 英文摘要 | Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg.kg(-1).d(-1), ig) for 4 weeks, their blood samples were analyzed. Results: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 mu mol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 mu mol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC(0-t)) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg.kg(-1).d(-1)) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg.kg(-1).d(-1), all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. Conclusion: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis. |
| WOS关键词 | SALT EXPORT PUMP ; CULTURED RAT HEPATOCYTES ; INDUCED LIVER-INJURY ; IN-VITRO ; RHEUMATOID-ARTHRITIS ; A77 1726 ; GENETIC-POLYMORPHISM ; ORAL TERIFLUNOMIDE ; METABOLITE A771726 ; ACTIVE METABOLITE |
| 资助项目 | National Science and Technology Program, China[2012ZX09301001-006] ; National Science and Technology Program, China[2012ZX09302003] ; National Science and Technology Program, China[2012ZX09301001] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2012ZX09303-001] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5652527 |
| WOS记录号 | WOS:000371426900014 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276126]  |
| 专题 | 药物安全性评价中心 |
| 通讯作者 | Luan, Yang; Pan, Guo-yu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Jiangsu Tripod Preclinical Res Labs Inc, Nanjing 211800, Jiangsu, Peoples R China; 3.Shanghai Jiao Tong Univ, Sch Med, Fac Publ Hlth, Shanghai 200025, Peoples R China; 4.Shanghai Jiao Tong Univ, Sch Med, Shanghai Tongren Hosp, Hongqiao Int Inst Med, Shanghai 200025, Peoples R China; 5.Jiangsu Univ, Inst Life Sci, Zhenjiang 212013, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Lei-lei,Wu, Zhi-tao,Wang, Le,et al. Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity[J]. ACTA PHARMACOLOGICA SINICA,2016,37(3):415-424. |
| APA | Ma, Lei-lei.,Wu, Zhi-tao.,Wang, Le.,Zhang, Xue-feng.,Wang, Jing.,...&Pan, Guo-yu.(2016).Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity.ACTA PHARMACOLOGICA SINICA,37(3),415-424. |
| MLA | Ma, Lei-lei,et al."Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity".ACTA PHARMACOLOGICA SINICA 37.3(2016):415-424. |
入库方式： OAI收割
来源：上海药物研究所
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