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Drug Metabolism and Disposition Fast Forward
First published on December 2, 2005; DOI: 10.1124/dmd.105.006213

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Received for publication June 27, 2005.
Revised November 21, 2005.
Accepted for publication November 22, 2005.

IN VITRO AND IN VIVO EVALUATION OF THE METABOLISM AND BIOAVAILABILITY OF ESTER PRODRUGS OF MSG0039, A POTENT MGLUR ANTAGONIST

Masato Nakamura 1*, Yasunori Kawakita 1, Akito Yasuhara 1, Yoshiki Fukasawa 1, Koji Yoshida 1, Kazunari Sakagami 1, Atsuro Nakazato 1

1 Taisho Pharmaceutical Co., Ltd.

* Address correspondence to: E-mail: masato.nakamura{at}po.rd.taisho.co.jp

Abstract

MGS0039 has been identified as a potent and selective antagonist for metabotropic glutamate receptors (mGluRs). However, the oral bioavailability of MGS0039 is 10.9% in rats, due to low absorption. Several prodrugs, synthesized to improve absorption, exhibited 40-70% bioavailability in rats. This study investigated in vitro metabolism using liver S9 fractions from both cynomolgus monkeys and humans and oral bioavailability in cynomolgus monkeys in order to select the prodrug most likely to exhibit optimal pharmacokinetic profiles in humans. In monkeys, transformation to active substance was observed (5.9-72.8%) in liver S9 fractions, and n-butyl, n-pentyl, 3-methylbutyl and 4-methylpentyl ester prodrugs exhibited high transformation ratios (> 64%). Cmax levels and F values following oral dosing increased to 4.1-6.3-fold and 2.4-6.3-fold, respectively, and a close relationship between transformation ratios and Cmax and F values was observed, indicating that the hydrolysis rate in liver S9 fractions is the key factor in determining oral bioavailability in monkeys. In humans n-hexyl, n-heptyl, n-octyl, 5-methylbutyl and 6-methylpentyl ester prodrugs exhibited high transformation ratios (> 65%) in liver S9 fractions. With these prodrugs, n-hexyl, n-heptyl and 5-methylpentyl ester, almost complete recovery (96-99%) was obtained. Given the transformation ratio, we anticipated that the n-heptyl alkyl ester prodrug would exhibit the highest oral bioavailability of active substances in humans, if the hydrolysis rate in liver S9 fractions is indeed the key factor in determining oral bioavailability in humans. On this basis, MGS0210 (n-heptyl alkyl ester prodrug) appears to be a promising candidate among MGS0039 prodrugs.


Key words: bioavailability, carboxylesterases, drug discovery, in vitro-in vivo prediction, prodrugs




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