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First published on March 31, 2005; DOI: 10.1124/dmd.104.002154

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Received for publication September 7, 2004.
Revised March 7, 2005.
Accepted for publication March 29, 2005.

Metabolic Profile of 1,5-Dicaffeoylquinic Acid in Rats, an in vivo and in vitro study

BO YANG 1, ZHIYUN MENG 2, JUNXING DONG 3, LIANGPING YAN 4, LIBO ZOU 4, ZHONGMING TANG 3, GUIFANG DOU 2*

1 Beijing Institute of Transfusion Medicine,Shenyang Pharmaceutical University 2 Beijing Institute of Transfusion Medicine 3 Beijing Institute of Radiation Medicine 4 Shenyang Pharmaceutical University

* Address correspondence to: E-mail: douguifang{at}vip.163.com

Abstract

To explore the metabolism of 1,5-dicaffeoylquinic acid (1,5-DCQA) in rats, liquid chromatography-mass spectrometry (LC-MS) in parallel to diode-array detection (DAD) was used for the rapid detection/characterization of the metabolites formed in bile, urine, and plasma of rats following oral administration of 1,5-DCQA (160 mg/kg). The methylation and glucuronidation of 1,5-DCQA occurring in vitro using rat liver and small intestinal microsomes and cytosols were studied in comparison with those occurring in vivo, and the enzymes involved were also determined. In addition, the anti-HIV (human immunodeficiency virus) activity of three important metabolites was preliminarily evaluated in MT-4 cells infected with HIV-1. A total of 22 metabolites in vivo and in vitro were identified, including four isomeric O-mono-methylated (M8-M11), nine isomeric O-di-methylated (M3, M6, M22, and M12-M17), four isomeric O-mono-methyl-glucuronidated (M2 and M19-M21), four isomeric O-di-methyl-glucuronidated (M1, M4, M5, and M7), and one glucuronidated (M18) metabolites. The O-methylation positions of three important metabolites (M8, M9, and M12) were determined (3''-, 3'-, and 3',3''-) by comparing with synthesized standards. The efficacy experiments showed that M8, M9 and M12 could inhibit HIV replication with IC50 values of about 25, 25 and 46 µM, respectively. These results suggest that O-methylation and glucuronidation are two important metabolic pathways of 1,5-DCQA, that both rat liver and small intestine can catalyze such reactions by catechol-O-methyltransferase (COMT) and UDP-glucuronosyltransferases (UGTs), and that the HIV-1 inhibitory activity of M8, M9 and M12 is comparable to or slightly weaker than that of 1,5-DCQA.


Key words: glucuronidation, HPLC, mass spectrometry, metabolite identification, methylation, phase II drug metabolism


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Y. Zeng, F. Qiu, Y. Liu, G. Qu, and X. Yao
Isolation and Identification of Phase 1 Metabolites of Demethoxycurcumin in Rats
Drug Metab. Dispos., September 1, 2007; 35(9): 1564 - 1573.
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