Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.
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 approximately 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 approximately 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.
James
Joyce K
JK
Merck Research Laboratories, Merck & Co., Inc., San Diego, CA 92121-1140, USA. Joyce_James@Merck.com
Nakamura
Masato
M
Nakazato
Atsuro
A
Zhang
Kanyin E
KE
Cramer
Merryl
M
Brunner
Janice
J
Cook
Jacquelynn
J
Chen
Weichao G
WG
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D004285:Dogs; D018690:Excitatory Amino Acid Agonists / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013045:Species Specificity; D013687:Telencephalon / Q000378:metabolism; D014018:Tissue Distribution
D001643:Bridged Bicyclo Compounds; D002250:Carbon Radioisotopes; D003998:Dicarboxylic Acids; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C418124:MGS 0028