title: In vitro and in vivo evaluation of the metabolism and bioavailability of ester prodrugs of mgs0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid), a potent metabotropic glutamate receptor antagonist.
abstract: MGS0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid) has been identified as a potent and selective antagonist for metabotropic glutamate receptors. However, the oral bioavailability of MGS0039 is 10.9% in rats, due to low absorption. Several prodrugs, synthesized to improve absorption, exhibited 40 to 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 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 after oral dosing increased to 4.1- to 6.3-fold and 2.4- to 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 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid n-heptyl ester) seems to be a promising candidate among MGS0039 prodrugs.
authors.affiliation: Medical Development Research Laboratories, Taisho Pharmaceutical Co., Ltd., 403 Yoshino-Cho 1-Chome, Kita-Ku, Saitama-Shi, Saitama, 331-9530, Japan. masato.nakamura@po.rd.taisho.co.jp
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kawakita
authors.forename: Akito
authors.initials: A
authors.lastname: Yasuhara
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Fukasawa
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kazunari
authors.initials: K
authors.lastname: Sakagami
authors.forename: Atsuro
authors.initials: A
authors.lastname: Nakazato
mesh_terms: D000818:Animals; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D003998:Dicarboxylic Acids / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: C483757:2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate