title: Renal tubular secretion of tanshinol: molecular mechanisms, impact on its systemic exposure, and propensity for dose-related nephrotoxicity and for renal herb-drug interactions.
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.
authors.affiliation: 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.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Jia
authors.affiliation: 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.
authors.forename: Feifei
authors.initials: F
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Junling
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Fengqing
authors.initials: F
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Olajide E
authors.initials: OE
authors.lastname: Olaleye
authors.affiliation: 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.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Dong
authors.affiliation: 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 chli@simm.ac.cn.
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002109:Caffeic Acids / Q000378:metabolism*; D002460:Cell Line; D005502:Food; D057809:HEK293 Cells; D041743:Herb-Drug Interactions / Q000502:physiology*; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002109:Caffeic Acids; D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; C585969:tanshinol; D011339:Probenecid