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.
Footnotes
-
This work was supported by Grant 2005CB523403 from the Chinese Ministry of Science and Technology and Grant 90209044 from the National Natural Science Foundation of China, and Grant 07G603J049 from the Shanghai Institute of Materia Medica/Chinese Academy of Sciences.
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.021592.
-
ABBREVIATIONS: PK, pharmacokinetic; TSL, tanshinol; PCA, protocatechuic aldehyde; SAA, salvianolic acid A; SAB, salvianolic acid B; SAD, salvianolic acid D; RMA, rosmarinic acid; LSA, lithospermic acid; LC/MS/MS, liquid chromatography/tandem mass spectrometry; AUC, area under concentration-time curve; CLtot,p, total plasma clearance; MRT, mean residence time; EH, hepatic extraction; CLR, renal clearance; P-gp, P-glycoprotein; MRP2, multidrug resistance-associated protein 2; fu, unbound fraction in plasma; LogD, distribution coefficient D; TPSA, topological polar surface area; NROTB, number of rotatable bonds.
- Received March 27, 2008.
- Accepted May 9, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|