The metabolism of YiGan San and subsequent pharmacokinetic evaluation of four metabolites in rat based on liquid chromatography with tandem mass spectrometry

• Published in: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Vol. 972; pp. 22 - 28
• Main Authors: Gai, Yanan, Chen, Han, Liu, Wenyuan, Feng, Feng, Xie, Ning
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2014
• Subjects: Animals; Benzofurans - urine; Chromatography; Chromatography, High Pressure Liquid - methods; Drugs, Chinese Herbal - analysis; Drugs, Chinese Herbal - pharmacokinetics; Ethers; High performance liquid chromatography; Indole Alkaloids - urine; Liquid chromatography; Liquids; Male; Mass spectrometry; Metabolites; Pharmacokinetics; Prototypes; Quadrupole mass spectrometry; Rats; Rats, Sprague-Dawley; Secologanin Tryptamine Alkaloids - urine; Tandem Mass Spectrometry - methods; Time-of-flight mass spectrometry; Urine; YiGan San; YiGan San; Quadrupole mass spectrometry; Metabolites; Pharmacokinetics; Time-of-flight mass spectrometry; High performance liquid chromatography
• ISSN: 1570-0232; 1873-376X
• DOI: 10.1016/j.jchromb.2014.09.033

•Metabolism of YiGan San in rat urine was investigated. Four metabolites were recognized and identified, their fragmentation pattern was summarized.•Pharmacokinetics of senkyunolide I, ajmalicine, isocorynoxeine and rhynchophylline in rat plasma were investigated. Concentration–time curves of the four compounds were plotted.•11-hydroxyhirsuteine was found presented in rat plasma 4h after administration.•Totally 51 compounds were identified in YGS and 18 of them were found in urine samples by proposed HPLC-Q-TOF-MS method. A new method based on liquid chromatography-tandem time-of-flight mass spectrometry was developed to identify the metabolites in rat urine after oral administration of YiGan San (YGS). Eighteen prototype compounds and four metabolites named 11-hydroxyhirsuteine, 19-carbonylhirsutine, 19-carbonyl-dihydrocorynantheine, and 18-hydroxy-geissoschizine methyl ether were identified. Subsequently, a method of high-performance liquid chromatography coupled with triple-quadrupole mass spectrometry was established for pharmacokinetic study of YGS in rat plasma. The concentration–time curves of four prototype compounds, senkyunolide I, ajmalicine, isocorynoxeine and rhynchophylline were constructed after an oral (9.1g YGS per kilogram of body weight) administration in rats. Method validation revealed excellent linearity over the range 220.00–0.55, 220.00–0.55, 21.40–0.05, and 19.80–0.05ng/mL for the four prototype compounds respectively. The stabilities results indicate that all of the analytes were stable in rat plasma in the autosampler for 24h, under freeze/thaw cycles (4 times in 24h), and at −20°C for one week. Residual analysis, heteroskedasticity test, and goodness-of-fit test were also performed to determine the accuracy of the linear regression method. The pharmacokinetic parameters were obtained. Four hours after administration, compound 11-hydroxyhirsuteine can be detected in rat plasma. Compared with purified ligustilide, YGS required a slightly longer period to reach maximum concentration (Cmax) in rat plasma.