RT Journal Article
SR Electronic
T1 Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 669
OP 678
DO 10.1124/dmd.114.062000
VO 43
IS 5
A1 Weiwei Jia
A1 Feifei Du
A1 Xinwei Liu
A1 Rongrong Jiang
A1 Fang Xu
A1 Junling Yang
A1 Li Li
A1 Fengqing Wang
A1 Olajide E. Olaleye
A1 Jiajia Dong
A1 Chuan Li
YR 2015
UL http://dmd.aspetjournals.org/content/43/5/669.abstract
AB 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.