PT - JOURNAL ARTICLE AU - Tong Lu AU - Junling Yang AU - Xiumei Gao AU - Ping Chen AU - Feifei Du AU - Yan Sun AU - Fengqing Wang AU - Fang Xu AU - Hongcai Shang AU - Yuhong Huang AU - Yi Wang AU - Renzhong Wan AU - Changxiao Liu AU - Boli Zhang AU - Chuan Li TI - Plasma and Urinary Tanshinol from <em>Salvia miltiorrhiza</em> (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine AID - 10.1124/dmd.108.021592 DP - 2008 Aug 01 TA - Drug Metabolism and Disposition PG - 1578--1586 VI - 36 IP - 8 4099 - http://dmd.aspetjournals.org/content/36/8/1578.short 4100 - http://dmd.aspetjournals.org/content/36/8/1578.full SO - Drug Metab Dispos2008 Aug 01; 36 AB - Cardiotonic pills are a type of cardiovascular herbal medicine. To identify suitable pharmacokinetic (PK) marker(s) for indicating systemic exposure to cardiotonic pills, we examined the in vivo PK properties of putatively active phenolic acids from the component herb Danshen (Radix Salviae miltiorrhizae). We also performed in vitro and in silico assessments of permeability and solubility. Several phenolic acids were investigated, including tanshinol (TSL); protocatechuic aldehyde (PCA); salvianolic acids A, B, and D; rosmarinic acid; and lithospermic acid. Plasma TSL exhibited the appropriate PK properties in dogs, including dose-dependent systemic exposure in area under concentration-time curve (AUC) and a 0.5-h elimination half-life. In rats, more than 60% of i.v. TSL was excreted intact into the urine. In humans, we found a significant correlation between the urinary recovery of TSL and its plasma AUC. The absorption rate and bioavailability of TSL were not significantly different whether cardiotonic pills were given p.o. or sublingually. The gender specificity in plasma AUC disappeared after body-weight normalization, but the renal excretion of TSL was significantly greater in women than in men. PCA was predicted to be highly permeable according to in vitro and in silico studies; however, extensive presystemic hepatic elimination and degradation in the erythrocytes led to extremely low plasma levels and poor dose proportionality. Integrated in vivo, in vitro, and in silico studies on the other phenolic acids showed poor gut permeability and nearly undetectable levels in plasma and urine. In conclusion, plasma and urinary TSL are promising PK markers for cardiotonic pills at the tested dose levels. The American Society for Pharmacology and Experimental Therapeutics