PT  - JOURNAL ARTICLE
AU  - Joyce K. James
AU  - Masato Nakamura
AU  - Atsuro Nakazato
AU  - Kanyin E. Zhang
AU  - Merryl Cramer
AU  - Janice Brunner
AU  - Jacquelynn Cook
AU  - Weichao G. Chen
TI  - METABOLISM AND DISPOSITION OF A POTENT GROUP II METABOTROPIC GLUTAMATE RECEPTOR AGONIST, IN RATS, DOGS, AND MONKEYS
AID  - 10.1124/dmd.105.004978
DP  - 2005 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1373--1381
VI  - 33
IP  - 9
4099  - http://dmd.aspetjournals.org/content/33/9/1373.short
4100  - http://dmd.aspetjournals.org/content/33/9/1373.full
SO  - Drug Metab Dispos2005 Sep 01; 33
AB  - Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1–10 mg/kg p.o.) in rats, with bioavailability >60% at all doses. However, bioavailability was only ∼20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey ≫ rat ∼ human ≫ dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development. The American Society for Pharmacology and Experimental Therapeutics