Pharmacokinetics and Metabolism of Ligustilide, a Major Bioactive Component in Rhizoma Chuanxiong, in the Rat

• Published in: Drug metabolism and disposition Vol. 36; no. 2; pp. 400 - 408
• Main Authors: RU YAN, NGA LING KO, LI, Song-Lin, YUN KAU TAM, GE LIN
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.02.2008
• Subjects: 4-Butyrolactone - administration & dosage; 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - blood; 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacokinetics; Animals; Biological and medical sciences; Drug Administration Routes; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacokinetics; Gastric Juice - chemistry; Intestinal Secretions - chemistry; Ligusticum - chemistry; Male; Medical sciences; Microsomes - metabolism; Pharmacology. Drug treatments; Plant Extracts - pharmacology; Rats; Rats, Sprague-Dawley; Vertebrata; Mammalia; Rat; Animal; Rodentia; Rhizome; Metabolism; Pharmacokinetics; Biological activity
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.107.017707

Ligustilide is the most abundant bioactive ingredient in Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular ailments. The present study reported, for the first time, the pharmacokinetics of ligustilide, administered in its pure form and in an herbal extract, in rats. After i.v. administration of pure ligustilide, it was distributed extensively (V d , 3.76 ± 1.23 l/kg) and eliminated rapidly ( t 1/2 , 0.31 ± 0.12 h). The i.v. clearance (CL) of ligustilide after Chuanxiong extract administration was significantly higher than that dosed in its pure form [CL, 20.35 ± 3.05 versus 9.14 ± 1.27 l/h/kg, p < 0.01; area under the curve (AUC), 0.79 ± 0.10 versus 1.81 ± 0.24 mg · h/l, p < 0.01], suggesting significant interaction between ligustilide and components present in the extract. Dose-dependent pharmacokinetics was observed after i.p. administration, and a significantly higher dose-normalized AUC (1.77 ± 0.23 mg · h/l) at 52 mg/kg was obtained than that at 26 mg/kg (0.93 ± 0.07 mg · h/l, p < 0.05). Oral bioavailability of ligustilide was low (2.6%), which was partly because of extensive first-pass metabolism in the liver. Seven metabolites of ligustilide were identified, and three of them were unequivocally characterized as butylidenephthalide, senkyunolide I, and senkyunolide H. These three compounds also occurred naturally in the herb and were reported to be bioactive.