The disposition, metabolism, and pharmacokinetics of a selective metabotropic glutamate receptor agonist in rats and dogs.
Compound LY354740 [(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid], an analog of glutamic acid, is a selective group 2 metabotropic glutamate receptor agonist in clinical development for the treatment of anxiety. Studies have been conducted to characterize the absorption, disposition, metabolism, and excretion of LY354740 in rats and dogs after intravenous bolus or oral administration. Plasma concentrations of LY354740 were measured using a validated gas chromatography/mass spectrometry assay. In rats, LY354740 demonstrated linear pharmacokinetics after oral administration from 30 to 1000 mg/kg. The oral bioavailability of LY354740 was approximately 10% in rats and 45% in dogs. In the dog, food decreased the mean area under the plasma concentration-time curve value by approximately 34%, hence, decreasing the oral bioavailability of the compound. Excretion studies in both rats and dogs indicate that the absorbed drug is primarily eliminated via renal excretion. In addition, tissue distribution in rats showed that the highest levels of radioactivity were in the kidney and gastrointestinal tract, which is consistent with the excretion studies. Metabolism of LY354740 was evaluated in vitro using rat and dog liver microsomes and rat liver slices. In addition, urine and fecal samples from rat and dog excretion studies were profiled using HPLC with radio-detection. These evaluations indicated that neither rats nor dogs metabolized LY354740. In summary, LY354740 is poorly absorbed in rats, moderately absorbed in dogs, and rapidly excreted as unchanged drug in the urine.
Johnson
Jason T
JT
Lilly Research Laboratories, Department of Drug Disposition, Eli Lilly and Company, Corporate Center, Indianapolis, IN 46285, USA.
Mattiuz
Edward L
EL
Chay
Sylvia H
SH
Herman
Jennifer L
JL
Wheeler
William J
WJ
Kassahun
Kelem
K
Swanson
Steven P
SP
Phillips
Diane L
DL
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D001798:Blood Proteins; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C104753:eglumetad