Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions
文献类型：期刊论文
| 作者 | Jia, Weiwei1,2; Du, Feifei2; Liu, Xinwei2; Jiang, Rongrong2; Xu, Fang2; Yang, Junling2 ; Li, Li2; Wang, Fengqing2; Olaleye, Olajide E.2; Dong, Jiajia2
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2015-05 |
| 卷号 | 43期号:5页码:669-678 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.114.062000 |
| 文献子类 | Article |
| 英文摘要 | Tanshinol has desirable antianginal and pharmacokinetic properties and is a key compound of Salvia miltiorrhiza roots (Danshen). It is extensively cleared by renal excretion. This study was designed to elucidate the mechanism underlying renal tubular secretion of tanshinol and to compare different ways to manipulate systemic exposure to the compound. Cellular uptake of tanshinol was mediated by human organic anion transporter 1 (OAT1) (K-m, 121 mu M), OAT2 (859 mu M), OAT3 (1888 mu M), and OAT4 (1880 mu M) and rat Oat1 (117 mu M), Oat2 (1207 mu M), and Oat3 (1498 mu M). Other renal transporters (human organic anion-transporting polypeptide 4C1 [OATP4C1], organic cation transporter 2 [OCT2], carnitine/organic cation transporter 1 [OCTN1], multidrug and toxin extrusion protein 1 [MATE1], MATE2-K, multidrug resistance-associated protein 2 [MRP2], MRP4, and breast cancer resistance protein [BCRP], and rat Oct1, Oct2, Octn1, Octn2, Mate1, Mrp2, Mrp4, and Bcrp) showed either ambiguous ability to transport tanshinol or no transport activity. Rats may be a useful model, to investigate the contribution of the renal transporters on the systemic and renal exposure to tanshinol. Probenecid-induced impairment of tubular secretion resulted in a 3- to 5-fold increase in the rat plasma area under the plasma concentration-time curve from 0 to infinity (AUC(0-infinity)) of tanshinol. Tanshinol exhibited linear plasma pharmacokinetic properties over a large intravenous dose range (2-200 mg/kg) in rats. The dosage adjustment could result in increases in the plasma AUC(0-infinity) of tanshinol of about 100-fold. Tanshinol exhibited very little dose-related nephrotoxicity. In summary, renal tubular secretion of tanshinol consists of uptake from blood, primarily by OAT1/Oat1, and the subsequent luminal efflux into urine mainly by passive diffusion. Dosage adjustment appears to be an efficient and safe way to manipulate systemic exposure to tanshinol. Tanshinol shows low propensity to cause renal transporter-mediated herb-drug interactions. |
| WOS关键词 | SALVIA-MILTIORRHIZA DANSHEN ; ORGANIC ANION TRANSPORTERS ; AQUEOUS EXTRACT ; GENE-EXPRESSION ; ACID-B ; RATS ; PHARMACOKINETICS ; INHIBITION ; IMMUNOLOCALIZATION ; GINSENOSIDES |
| 资助项目 | National Natural Science Fund of China for Distinguished Young Scholars[30925044] ; National Science and Technology Major Project of China "Key New Drug Creation and Manufacturing Program"[2009ZX09304-002] ; National Basic Research Program of China[2012CB518403] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000352002800003 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276562]  |
| 专题 | 上海药物代谢研究中心 科研与新药推进处 |
| 通讯作者 | Li, Chuan |
| 作者单位 | 1.Tianjin Univ Tradit Chinese Med, Grad Sch, Tianjin, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.China Acad Chinese Med Sci, Inst Chinese Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Jia, Weiwei,Du, Feifei,Liu, Xinwei,et al. Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions[J]. DRUG METABOLISM AND DISPOSITION,2015,43(5):669-678. |
| APA | Jia, Weiwei.,Du, Feifei.,Liu, Xinwei.,Jiang, Rongrong.,Xu, Fang.,...&Li, Chuan.(2015).Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions.DRUG METABOLISM AND DISPOSITION,43(5),669-678. |
| MLA | Jia, Weiwei,et al."Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions".DRUG METABOLISM AND DISPOSITION 43.5(2015):669-678. |
入库方式： OAI收割
来源：上海药物研究所
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