Received for publication March 27, 2008.
Revised May 7, 2008.
Accepted for publication May 9, 2008.

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 marker(s) for indicating systemic exposure to Cardiotonic pills, we examined the in vivo pharmacokinetic 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, protocatechuic aldehyde, salvianolic acids A, B, and D, rosmarinic acid, and lithospermic acid. Plasma tanshinol exhibited the appropriate pharmacokinetic 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, over 60% of intravenous tanshinol was excreted intact into the urine. In humans, we found a significant correlation between the urinary recovery of tanshinol and its plasma AUC. The absorption rate and bioavailability of tanshinol were not significantly different whether Cardiotonic pills were given orally or sublingually. The gender-specificity in plasma AUC disappeared after body-weight normalization, but the renal excretion of tanshinol was significantly greater in women than in men. Protocatechuic aldehyde 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 tanshinol are promising pharmacokinetic markers for Cardiotonic pills at the tested dose levels.

Key words: absorption, drug disposition, excretion, gender differences, half-life, human pharmacokinetics, mass spectrometry, oral absorption, pharmacokinetics, renal elimination