Extremely Low Bioavailability of Magnesium Lithospermate B, An Active Component from Salvia miltiorrhiza, in Rat

Abstract

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 ± 10.9 and 1130 ± 329 μg·min/mL), total body clearance (CL_tot; 55.52 ± 7.07 and 23.51 ± 5.98 mL/min/kg), and distribution volume at steady state (V_ss; 7.60 ± 1.03 and 3.61 ± 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 ± 0.36 μg·min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % ± 0.26 % and 5.10 % ± 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL_tot and V_ss values, and were much less (0.010 % ± 0.001 % and 0.12 % ± 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.

Key words

Salvia miltiorrhiza - Labiatae (Lamiaceae) - magnesium lithospermate B - pharmacokinetics - bioavailability - absorption - excretion

References

• 1 Li L N. Biologically active components from traditional Chinese medicines.  Pure Appl Chem. 1998;  70 547-54
• 2 Chang H M, Cheng K P, Choang T F, Chow H F, Chui K Y, Hon P M. et al . Structure elucidation and total synthesis of new tanshinones isolated from Salvia miltiorrhiza Bunge (Danshen).  J Org Chem. 1990;  55 3537-43
• 3 Zhang K Q, Bao Y, Wu P, Rosen R T, Ho C T. Antioxidative components of danshen (Salvia miltiorrhiza Bunge).  J Agric Food Chem. 1990;  38 1194-7
• 4 Zhang B, Liu L. Advances in the study of pharmacological actions of water soluble constituents of danshen (Salvia miltiorrhiza).  Zhong-Cao-Yao (Chinese Traditional and Herbal Drugs). 1996;  27 634-6
• 5 Lu Y, Foo L Y. Polyphenolics of Saliva - a review.  Phytochemistry. 2002;  59 117-40
• 6 Kasimu R, Tanaka K, Tezuka Y, Gong Z N, Li J X, Basnet P. et al . Comparative study of seventeen Salvia plants: aldose reductase inhibitory activity of water and MeOH extracts and liquid chromatography-mass spectrometry (LC-MS) analysis of water extracts.  Chem Pharm Bull. 1998;  46 500-4
• 7 Huang Y S, Zhang J T. Antioxidative effect of three water-soluble components isolated from Salvia miltiorrhiza in vitro .  Yaoxue Xuebao (Acta Pharmaceutica Sinica). 1992;  27 96-100
• 8 Chen C P, Yokozawa T, Chung H Y. Inhibitor effect of caffeic acid analogues isolated from Salviae Miltiorrhizae Radix against 1,1-diphenyl-2-picrylhydrazyl radical.  Exp Toxicol Pathol. 1999;  51 59-63
• 9 Shigematsu T, Tajima S, Nishikawa T, Murad S, Pinnell S R, Nishioka 1. Inhibition of collagen hydroxylation by lithospermic acid magnesium salt, a novel compound isolated from Salviae miltiorrhizae Radix.  Biochim Biophys Acta. 1994;  1200 79-83
• 10 Fung K P, Zeng L H, Wu J, Wong H NC, Lee C M, Hon P M. et al . Demonstration of the myocardial salvage effect of lithospermic acid B isolated from the aqueous extract of Salvia miltiorrhiza .  Life Sci. 1993;  52 PL239-44
• 11 Hase K, Kasimu R, Basent P, Kadota S, Namba T. Preventive effect of lithospermate B from Salvia miltiorrhiza on experimental hepatitis induced by carbon tetrachloride or D-galactosamine/lipopolysaccharide.  Planta Med. 1997;  63 22-6
• 12 Tanaka T, Morimoto S, Nonaka G, Nishioka I, Yokozawa T, Chung H Y, Oura H. Magnesium and ammonium-potassium lithospermates B, the active principles having a uremia-preventive effect from Salvia miltiorrhiza .  Chem Pharm Bull. 1989;  37 340-4
• 13 Yokozawa T, Lee T W, Chung H Y, Oura H, Nonaka G, Nishioka 1. Depressor effect of magnesium lithospermate B, a component of Salviae Miltiorrhizae Radix, in spontaneously hypertensive rats.  Phytother Res. 1994;  8 271-5
• 14 Yokozawa T, Zhou J J, Oura H, Tanaka T, Nonaka G, Nishioka I. Effects on blood pressure of caffeic acid analogues isolated from Salviae Miltiorrhizae Radix in rats with adenine-induced renal hypertension.  Phytother Res. 1995;  9 105-9
• 15 Yokozawa T, Oura H, Lee T W, Nonaka G, Nishioka I. Augmentation of renal response by magnesium lithospermate B.  Nephron. 1991;  57 78-83
• 16 Akao T, Kawabata K, Yanagisawa E, Ishihara K, Mizuhara Y, Wakui Y et a l. Baicalin, the predominant flavone glucuronide of Scutellariae Radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form.  J Pharm Pharmacol. 2000;  52 1563-8
• 17 Azuma K, Ippoushi K, Nakayama M, Ito H, Higashio H, Terao I. Absorption of chlorogenic acid and caffeic acid in rats after oral administration.  J Agric Food Chem. 2000;  48 5496-500
• 18 Olthof M R, Hollman P CH, Katan M B. Chlorogenic acid and caffeic acid are absorbed in humans.  J Nutr. 2001;  131 66-71
• 19 Scalbert A, Morand C, Manach C, Romesy C. Absorption and metabolism of polyphenols in the gut and impact on health.  Biomed Pharmacother. 2002;  56 276-82
• 20 Giugliano D. Dietary antioxidants for cardiovascular prevention.  Nutr Metab Cardiovasc Dis. 2000;  10 38-44