Planta Med 2013; 79(16): 1536-1544
DOI: 10.1055/s-0033-1350796
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

In Vitro Metabolism of Pyranocoumarin Isomers Decursin and Decursinol Angelate by Liver Microsomes from Man and Rodents

Li Li
1   Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas, USA
,
Jinhui Zhang
1   Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas, USA
,
Chengguo Xing
2   Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA
,
Sung-Hoon Kim
3   Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University, Seoul, Republic of Korea
,
Cheng Jiang
1   Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas, USA
,
Junxuan Lü
1   Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas, USA
› Author Affiliations
Further Information

Publication History

received 06 May 2013
revised 31 July 2013

accepted 07 August 2013

Publication Date:
11 September 2013 (online)

Abstract

The aim of this study is to investigate and compare the metabolic rate and profiles of pyranocoumarin isomers decursin and decursinol angelate using liver microsomes from humans and rodents, and to characterize the major metabolites of decursin and decursinol angelate in human liver microsomal incubations using LC-MS/MS. First, we conducted liver microsomal incubations of decursin and decursinol angelate in the presence or absence of NADPH. We found that in the absence of NADPH, decursin was efficiently hydrolyzed to decursinol by hepatic esterase(s), but decursinol angelate was not. In contrast, formation of decursinol from decursinol angelate was mediated mainly by cytochrome P450(s). Second, we measured the metabolic rate of decursin and decursinol angelate in liver S9 fractions from mice and humans. We found that human liver S9 fractions metabolized both decursin and decursinol angelate more slowly than those of the mouse. Third, we characterized the major metabolites of decursin and decursinol angelate from human liver microsomes incubations using HPLC-UV and LC-MS/MS methods and assessed the in vivo metabolites in mouse plasma from a one-dose PK study. Decursin and decursinol angelate have different metabolite profiles. Nine metabolites of decursin and nine metabolites of decursinol angelate were identified in human liver microsome incubations besides decursinol using a hybrid triple quadruple linear ion trap LC-MS/MS system, and many of them were later verified to be also present in plasma samples from rodent PK studies.

Supporting Information

 
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