Methylation and its role in the disposition of tanshinol, a cardiovascular carboxylic catechol from Salvia miltiorrhiza roots （Danshen）  

作　　者：Dan-dan TIAN Wei-wei JIA Xin-wei LIU Dan-dan WANG Jun-hua LIU Jia-jia DONG Li LI Fei-fei DU Fang XU Feng-qing WANG Yan SUN Yu-xing HUANG Mei-juan LI Li-hong HU Yan ZHU Xiu-mei GAO Chuan LI Jun-ling YANG 

机构地区：[1]Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]University of Chinese Academy of Sciences, Shanghai 201203, China [3]Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China [4]Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

出　　处：《Acta Pharmacologica Sinica》2015年第5期627-643,共17页中国药理学报（英文版）

摘　　要：Aim： Tanshinol is an important catechol in the antianginal herb Salvia miltiorrhiza roots （Danshen）. This study aimed to characterize tanshinol methylation. Methods： Metabolites of tanshinol were analyzed by liquid chromatography/mass spectrometry. Metabolism was assessed in vitro with rat and human enzymes. The major metabolites were synthesized for studying their interactions with drug metabolizing enzymes and transporters and their vasodilatory properties. Dose-related tanshinol methylation and its influences on tanshinol pharmacokinetics were also studied in rats. Results： Methylation, preferentially in the 3-hydroxyl group, was the major metabolic pathway of tanshinol. In rats, tanshinol also underwent considerable 3-O-sulfation, which appeared to be poor in human liver. These metabolites were mainly eliminated via renal excretion, which involved tubular secretion mainly by organic anion transporter （OAT） 1. The methylated metabolites had no vasodilatory activity. Entacapone-impaired methylation did not considerably increase systemic exposure to tanshinol in rats. The saturation of tanshinol methylation in rat liver could be predicted from the Michaelis constant of tanshinol for catechol-O-methyltransferase （COMT）. Tanshinol had low affinity for human COMT and OATs; its methylated metabolites also had low affinity for the transporters. Tanshinol and its major human metabolite （3-O-methyltanshinol） exhibited negligible inhibitory activities against human cytochrome P450 enzymes, organic anion transporting polypeptides 1B1/1B3, multidrug resistance protein 1, multidrug resistance-associated protein 2, and breast cancer resistance protein. Conclusion： Tanshinol is mainly metabolized via methylation. Tanshinol and its major human metabolite have low potential for pharmacokinetic interactions with synthetic antianginal agents. This study will help define the risk of hyperhomocysteinemia related to tanshinol methylation.Aim： Tanshinol is an important catechol in the antianginal herb Salvia miltiorrhiza roots （Danshen）. This study aimed to characterize tanshinol methylation. Methods： Metabolites of tanshinol were analyzed by liquid chromatography/mass spectrometry. Metabolism was assessed in vitro with rat and human enzymes. The major metabolites were synthesized for studying their interactions with drug metabolizing enzymes and transporters and their vasodilatory properties. Dose-related tanshinol methylation and its influences on tanshinol pharmacokinetics were also studied in rats. Results： Methylation, preferentially in the 3-hydroxyl group, was the major metabolic pathway of tanshinol. In rats, tanshinol also underwent considerable 3-O-sulfation, which appeared to be poor in human liver. These metabolites were mainly eliminated via renal excretion, which involved tubular secretion mainly by organic anion transporter （OAT） 1. The methylated metabolites had no vasodilatory activity. Entacapone-impaired methylation did not considerably increase systemic exposure to tanshinol in rats. The saturation of tanshinol methylation in rat liver could be predicted from the Michaelis constant of tanshinol for catechol-O-methyltransferase （COMT）. Tanshinol had low affinity for human COMT and OATs; its methylated metabolites also had low affinity for the transporters. Tanshinol and its major human metabolite （3-O-methyltanshinol） exhibited negligible inhibitory activities against human cytochrome P450 enzymes, organic anion transporting polypeptides 1B1/1B3, multidrug resistance protein 1, multidrug resistance-associated protein 2, and breast cancer resistance protein. Conclusion： Tanshinol is mainly metabolized via methylation. Tanshinol and its major human metabolite have low potential for pharmacokinetic interactions with synthetic antianginal agents. This study will help define the risk of hyperhomocysteinemia related to tanshinol methylation.

关 键 词：tanshinol METHYLATION CATECHOL-O-METHYLTRANSFERASE herb-drug interaction Salvia miltiorrhiza roots DANSHEN 

分 类 号：Q754[生物学—分子生物学] TQ461[化学工程—制药化工]