Relative contributions of presystemic and systemic peptidases to oral exposure of a novel metabotropic glutamate 2/3 receptor agonist (LY404039) after oral administration of prodrug pomaglumetad methionil (LY2140023).
Pomaglumetad methionil (LY2140023) is the prodrug of a novel metabotropic glutamate 2/3 receptor agonist (LY404039) being investigated for the treatment of schizophrenia. Using accelerator mass spectrometry (AMS) and an intravenous (i.v.) radiolabeled tracer approach, the absolute bioavailability of the prodrug and the extent of its conversion to active moiety (LY404039) were estimated at presystemic (intestinal/first pass) and systemic sites after simultaneous oral and i.v. dosing in healthy subjects. The mean absolute bioavailability of prodrug (80 mg oral) was 0.68. On the basis of these data and a previous radiolabeled mass balance study in which no prodrug was recovered in feces, we concluded that 0.32 of the dose is converted to active drug in the intestinal tract. The fraction of prodrug converted to active moiety was approximately 1, indicating complete conversion of the prodrug that reaches the systemic circulation to the active moiety. Prodrug (80 mg oral and 100 μg i.v.) and active moiety (100 μg i.v.) were well tolerated in healthy subjects. Thus, the absolute bioavailability of prodrug LY2140023 and the fraction converted presystemically and systemically to active moiety LY404039 were estimated simultaneously using radiolabeled tracer microdosing and AMS.
Eli Lilly and Company, Indianapolis, Indiana, 46285.
William F
WF
Annes
Amanda
A
Long
Jennifer W
JW
Witcher
Mosun A
MA
Ayan-Oshodi
Mary Pat
MP
Knadler
Wei
W
Zhang
Malcolm I
MI
Mitchell
Karen
K
Cornelissen
Stephen D
SD
Hall
D065767:Activation, Metabolic; D000284:Administration, Oral; D000328:Adult; D000596:Amino Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D018592:Cross-Over Studies; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D006801:Humans; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010447:Peptide Hydrolases / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D055815:Young Adult
C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D000596:Amino Acids; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D003499:Cyclic S-Oxides; C534551:LY 2140023; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D010447:Peptide Hydrolases
ADME; accelerator mass spectrometry; bioavailability; pharmacokinetics; prodrug activation