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Research ArticleArticle

Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions

Weiwei Jia, Feifei Du, Xinwei Liu, Rongrong Jiang, Fang Xu, Junling Yang, Li Li, Fengqing Wang, Olajide E. Olaleye, Jiajia Dong and Chuan Li
Drug Metabolism and Disposition May 2015, 43 (5) 669-678; DOI: https://doi.org/10.1124/dmd.114.062000
Weiwei Jia
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Feifei Du
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Xinwei Liu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Rongrong Jiang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Fang Xu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Junling Yang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Li Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Fengqing Wang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Olajide E. Olaleye
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Jiajia Dong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Chuan Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (W.J., F.D., X.L., R.J., F.X., J.Y., L.L., F.W., O.E.O., J.D., C.L.); Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin (W.J.); Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing (C.L.), People’s Republic of China
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Abstract

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) (Km, 121 μM), OAT2 (859 μM), OAT3 (1888 μM), and OAT4 (1880 μM) and rat Oat1 (117 µM), Oat2 (1207 μM), and Oat3 (1498 μM). 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 (AUC0–∞) 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 AUC0–∞ 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.

Footnotes

    • Received November 7, 2014.
    • Accepted February 20, 2015.
  • This work was supported by grants from the National Natural Science Fund of China for Distinguished Young Scholars [Grant 30925044], the National Science and Technology Major Project of China “Key New Drug Creation and Manufacturing Program” [Grant 2009ZX09304-002], and the National Basic Research Program of China [Grant 2012CB518403].

  • Part of this work was previously presented as follows: Jia W-W et al. Renal organic anion transporter 1 (Oat1) as a determinant of rat systemic exposure to tanshinol of Salvia miltiorrhiza. Poster presentation at the 2nd Annual Shanghai Symposium on Chemical and Pharmaceutical Solutions through Analysis (CPSA); 2011 Apr 13–16; Shanghai, People’s Republic of China.

  • dx.doi.org/10.1124/dmd.114.062000.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (5)
Drug Metabolism and Disposition
Vol. 43, Issue 5
1 May 2015
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Research ArticleArticle

Renal Tubular Secretion of Tanshinol

Weiwei Jia, Feifei Du, Xinwei Liu, Rongrong Jiang, Fang Xu, Junling Yang, Li Li, Fengqing Wang, Olajide E. Olaleye, Jiajia Dong and Chuan Li
Drug Metabolism and Disposition May 1, 2015, 43 (5) 669-678; DOI: https://doi.org/10.1124/dmd.114.062000

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Research ArticleArticle

Renal Tubular Secretion of Tanshinol

Weiwei Jia, Feifei Du, Xinwei Liu, Rongrong Jiang, Fang Xu, Junling Yang, Li Li, Fengqing Wang, Olajide E. Olaleye, Jiajia Dong and Chuan Li
Drug Metabolism and Disposition May 1, 2015, 43 (5) 669-678; DOI: https://doi.org/10.1124/dmd.114.062000
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