Skip to main content
PMC home page
Current Therapeutic Research, Clinical and Experimental logoLink to Current Therapeutic Research, Clinical and Experimental
. 2010 Aug;71(4):260–271. doi: 10.1016/j.curtheres.2010.08.004

Pharmacokinetics of depside salts from Salvia miltiorrhiza in healthy Chinese volunteers: A randomized, open-label, single-dose study

Jing-Ying Jia 1, You-Li Lu 2, Xiao-Chuan Li 2, Gang-Yi Liu 1, Shui-Jun Li 1,2, Yun Liu 1, Yan-Mei Liu 1, Chen Yu 1, Yi-Ping Wang 2,*
PMCID: PMC3969617  PMID: 24688148

Abstract

Background: Depside salts from Salvia miltiorrhiza, with active components of lithospermic acid B (LSB), rosmarinic acid (RA), and lithospermic acid (LA), are a multicomponent drug marketed in China for the treatment of coronary heart disease.

Objectives: The aims of this study were to determine the concentrations of LSB, RA, and LA in human plasma and urine, and to compare the pharmacokinetic properties of depside salts from S miltiorrhiza in healthy Chinese volunteers.

Methods: A randomized, open-label, single-dose study was conducted in healthy Chinese volunteers. Participants were randomly assigned to receive a single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza. Blood was collected through a venous cannula prior to study drug administration (0 min) and at 10, 20, 30, 60, 65, 70, 80, and 90 minutes and 2, 3, 4, 6, 8, 12, and 24 hours after study drug administration. Urine samples were taken before study drug administration (0) and at 0 to 12 and 12 to 24 hours after study drug administration. LSB, RA, and LA concentrations in serum and urine were analyzed by an LC-MS/MS method. Tolerability was determined by clinical assessment; vital signs (ie, blood pressure, heart rate, breathing rate, body temperature) monitoring at baseline and at the end of the study, clinical laboratory tests (ie, hematology, blood biochemistry, hepatic function, renal function, urinalysis), 12-lead ECG measurements, and physical examinations at baseline and after completion of the study.

Results: Twelve Chinese volunteers (6 males, 6 females; mean [SD] age, 25.2 [3.8] years; mean height, 165.7 [8.9] cm; mean body mass index, 21.6 [2.5] kg/m2) were enrolled in the study. Peak plasma concentrations of LSB, RA and LA were observed at 0.3 to 1 hour following the 1-hour intravenous infusion, with respective mean (SD) Cmax of 4925 (1861), 174 (61), and 361 (101) ng/mL for the 100-mg dose and 10,285 (2259), 308 (77), and 674 (85) ng/mL for the 200-mg dose. The AUClast values for LSB, RA, and LA were 4537 (1265), 129 (28), and 1229 (330) ng/mL/h, respectively, for the 100-mg dose and 10,426 (2589), 260 (53), and 2792 (729) ng/mL/h for the 200-mg dose. No significant difference in pharmacokinetic parameters was observed between male and female subjects. Three metabolites were found in the plasma with low concentrations. The urinary excretion recoveries of LSB, RA, and LA were 0.58% (0.42%), 25.21% (20.61%), and 10.02% (7.72%) for the 100-mg dose and 0.38% (0.18%), 20.11% (10.50%), and 6.34% (3.20%) for the 200-mg dose. No adverse events were reported by the subjects or found by the investigators in the analysis of vital signs, 12-lead ECG measurements, physical examinations, or clinical laboratory tests.

Conclusions: Following single intravenous infusion of 100 or 200 mg of depside salts from S miltiorrhiza to healthy Chinese subjects, no statistical differences in pharmacokinetic parameters were observed between males and females. The 2 doses of depside salts from S miltiorrhiza were clinically well tolerated during the study.

Key words: lithospermic acid B, rosmarinic acid, lithospermic acid, pharmacokinetics, healthy volunteers, liquid chromatography tandem mass spectrometry, LC-MS/MS

Full Text

The Full Text of this article is available as a PDF (647.8 KB).

References

  • 1.Li LN. Biologically active components from traditional Chinese medicines. Pure Appl Chem. 1998;70:547–554. [Google Scholar]
  • 2.Li X, Yu C, Lu Y. Pharmacokinetics, tissue distribution, metabolism, and excretion of depside salts from Salvia miltiorrhiza in rats. Drug Metab Dispos. 2007;35:234–239. doi: 10.1124/dmd.106.013045. [DOI] [PubMed] [Google Scholar]
  • 3.Li XF, Wang YP. Depside salts from Salvia miltiorrhiza improve myocardial microperfusion in rats using laser Doppler flowmetry. Acta Pharmacol Sin. 2007;28:789–795. doi: 10.1111/j.1745-7254.2007.00546.x. [DOI] [PubMed] [Google Scholar]
  • 4.Zupkó I, Hohmann J, Rédei D. Antioxidant activity of leaves of Salvia species in enzyme-dependent and enzyme-independent systems of lipid peroxidation and their phenolic constituents. Planta Med. 2001;67:366–368. doi: 10.1055/s-2001-14327. [DOI] [PubMed] [Google Scholar]
  • 5.Yokozawa T, Chung HY, Dong E, Oura H. Confirmation that magnesium lithospermate B has a hydroxyl radical-scavenging action. Exp Toxicol Pathol. 1995;47:341–344. doi: 10.1016/S0940-2993(11)80344-1. [DOI] [PubMed] [Google Scholar]
  • 6.Kang DG, Oh H, Sohn EJ. Lithospermic acid B isolated from Salvia miltiorrhiza ameliorates ischemia/reperfusion-induced tenal injury in rats. Life Sci. 2004;75:1801–1816. doi: 10.1016/j.lfs.2004.02.034. [DOI] [PubMed] [Google Scholar]
  • 7.Yokozawa T, Oura H, Lee TW. Augmentation of renal response by magnesium lithospermate B. Nephron. 1991;57:78–83. doi: 10.1159/000186221. [DOI] [PubMed] [Google Scholar]
  • 8.Yokozawa T, Lee TW, Oura H. Effect of magnesium lithospermate B in rats with sodiuminduced hypertension and renal failure. Nephron. 1992;60:460–465. doi: 10.1159/000186809. [DOI] [PubMed] [Google Scholar]
  • 9.Yokozawa T, Dong E, Liu ZW. Magnesium lithospermate B ameliorates cephaloridineinduced renal injury. Exp Toxicol Pathol. 1997;49:337–341. doi: 10.1016/S0940-2993(97)80100-5. [DOI] [PubMed] [Google Scholar]
  • 10.Fung KP, Zeng LH, Wu J. Demonstration of the myocardial salvage effect of lithospermic acid B isolated from the aqueous extract of Salvia miltiorrhiza. Life Sci. 1993;52:PL239–PL244. doi: 10.1016/0024-3205(93)90471-e. [DOI] [PubMed] [Google Scholar]
  • 11.Hase K, Kasimu R, Basnet P. Preventive effect of lithospermate B from Salvia miltiorrhiza on experimental hepatitis induced by carbon tetrachloride or D-galactosamine/lipopolysaccharide. Planta Med. 1997;63:22–26. doi: 10.1055/s-2006-957596. [DOI] [PubMed] [Google Scholar]
  • 12.Parnham MJ, Kesselring K. Rosmarinic acid. Drugs Future. 1985;10:756–757. [Google Scholar]
  • 13.Chen L, Wang WY, Wang YP. Inhibitory effects of lithospermic acid on proliferation and migration of rat vascular smooth muscle cells. Acta Pharmacol Sin. 2009;30:1245–1252. doi: 10.1038/aps.2009.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Miao Y, Gao Z, Xu F. Clinical observation on Salvianolate for the treatment of angina pectoris in coronary heart disease with heart-blood stagnation syndrome. Trad Chin Drug Res Clin Pharmacol. 2006;17:140–144. [Google Scholar]
  • 15.Zhang Y, Akao T, Nakamura N. Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat. Planta Med. 2004;70:138–142. doi: 10.1055/s-2004-815490. [DOI] [PubMed] [Google Scholar]
  • 16.Zhang Y, Akao T, Nakamura N. Magnesium lithospermate B is excreted rapidly into rat bile mostly as methylated metabolites, which are potent antioxidants. Drug Metab Dispos. 2004;32:752–757. doi: 10.1124/dmd.32.7.752. [DOI] [PubMed] [Google Scholar]
  • 17.Li X, Yu C, Sun W. Simultaneous determination of magnesium lithospermate B, rosmarinic acid, and lithospermic acid in beagle dog serum by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2004;18:2878–2882. doi: 10.1002/rcm.1703. [DOI] [PubMed] [Google Scholar]

Articles from Current Therapeutic Research, Clinical and Experimental are provided here courtesy of Elsevier

RESOURCES