RT Journal Article
SR Electronic
T1 Plasma and Urinary Tanshinol from <em>Salvia miltiorrhiza</em> (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1578
OP 1586
DO 10.1124/dmd.108.021592
VO 36
IS 8
A1 Tong Lu
A1 Junling Yang
A1 Xiumei Gao
A1 Ping Chen
A1 Feifei Du
A1 Yan Sun
A1 Fengqing Wang
A1 Fang Xu
A1 Hongcai Shang
A1 Yuhong Huang
A1 Yi Wang
A1 Renzhong Wan
A1 Changxiao Liu
A1 Boli Zhang
A1 Chuan Li
YR 2008
UL http://dmd.aspetjournals.org/content/36/8/1578.abstract
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