title: Plasma and urinary tanshinol from Salvia miltiorrhiza (Danshen) can be used as pharmacokinetic markers for cardiotonic pills, a cardiovascular herbal medicine.
abstract: 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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Lu
authors.forename: Junling
authors.initials: J
authors.lastname: Yang
authors.forename: Xiumei
authors.initials: X
authors.lastname: Gao
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Feifei
authors.initials: F
authors.lastname: Du
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Fengqing
authors.initials: F
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Hongcai
authors.initials: H
authors.lastname: Shang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Huang
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Renzhong
authors.initials: R
authors.lastname: Wan
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
authors.forename: Boli
authors.initials: B
authors.lastname: Zhang
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
mesh_terms: D045784:Abietanes; D000818:Animals; D018938:Caco-2 Cells; D002109:Caffeic Acids / Q000493:pharmacokinetics; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004285:Dogs; D006801:Humans; D008297:Male; D010616:Phenanthrenes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D045784:Abietanes; D002109:Caffeic Acids; D002316:Cardiotonic Agents; D010616:Phenanthrenes; C585969:tanshinol; C021751:tanshinone