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Drug Metabolism and Disposition Fast Forward
First published on November 15, 2007; DOI: 10.1124/dmd.107.019059

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Takahiro Murai
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Received for publication October 15, 2007.
Revised November 11, 2007.
Accepted for publication November 12, 2007.

Isolation and Identification of Diglucuronides of Some Endogenous Steroids in Dogs

Takahiro Murai 1*, Naotoshi Yamamura 1, Takashi Nitanai 1, Naozumi Samata 2, Makoto Takei 1, Haruo Iwabuchi 1, Kohji Tanaka 1, Kei Mikamoto 1, Toshihiko Ikeda 3

1 Daiichi Sankyo Co., Ltd. 2 Daiichi Sankyo RD Associe Co., Ltd. 3 Association for Promoting Drug Development

* Address correspondence to: E-mail: murai.takahiro.a4{at}daiichisankyo.co.jp

Abstract

Diglucuronidation is a novel glucuronidation reaction where the second glucuronosyl moiety is attached at the C2' position of the first glucuronosyl moiety. In order to examine whether diglucuronidation takes place in endogenous substrates in vivo, control urine and bile samples were collected from male Crl:CD(SD) IGS rats, beagle dogs and cynomolgus monkeys and analyzed by liquid chromatography-mass spectrometry (LC-MS) after solid phase extraction. Several diglucuronides of C19 steroids, including M1 (C31H46O14) and M2 (C31H44O14), were detected in the urine and bile of the dogs, but not in the excreta of the rats and monkeys. A milligram quantity of M1 was successfully isolated from the pooled dog urine and analyzed by nuclear magnetic resonance (NMR) spectroscopy. M1 was unambiguously identified as epiandrosterone 3-O-diglucuronide by comparing the LC-MS and two-dimensional NMR data of M1 with those of the biosynthesized epiandrosterone 3-O-diglucuronide. M2 was identified as dehydroepiandrosterone 3-O-diglucuronide. According to these findings, the diglucuronidation reaction was proven to be occurring on steroid hormones in vivo in dogs.


Key words: glucuronidation, mass spectrometry, metabolite identification, microsomes, steroids




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