The Disposition, Metabolism, and Pharmacokinetics of a Selective Metabotropic Glutamate Receptor Agonist in Rats and Dogs

Abstract

This paper is available online at http://dmd.aspetjournals.org ABSTRACT: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.

Pharmacokinetics, Metabolism, and Excretion of the Intestinal Peptide Transporter 1 (SLC15A1)-Targeted Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2-Amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid (LY544344) in Rats and Dogs: Assessment of First-Pass Bioactivation and Dose Linearity

“…The lack of further metabolism and the patterns of excretion are similar to previous data for LY354740 (Johnson et al, 2002). Therefore, due to the nearly complete first-pass hydrolysis of LY544344, the pharmacokinetics of the active LY354740 is the best measure of the prodrug's performance in vivo.…”

“…1) is a potent and selective agonist of group II/cAMP-coupled metabotropic glutamate (mGlu2/3) receptors, with anxiolytic activity in numerous animal models (Schoepp et al, 1997(Schoepp et al, , 2003. Although LY354740 is highly soluble and not metabolized in any studied species, its bioavailability ranged from only 10% in rats to 45% in dogs (Johnson et al, 2002) and was similarly low in humans (Kellner et al, 2005). The low systemic availability of LY354740 appears to be due to poor intestinal permeability, related to its low molecular weight, zwitterionic character, and polarity.…”

Pharmacological and Pharmacokinetic Properties of a Structurally Novel, Potent, and Selective Metabotropic Glutamate 2/3 Receptor Agonist: In Vitro Characterization of Agonist (–)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic Acid (LY404039)

“…We report here that LY404039 effectively modulates mGlu2/3 receptors in situ with a potency similar to that previously reported for LY354740, suggesting that this compound should also demonstrate efficacy in animal models of psychosis and anxiety. Perhaps most importantly, we demonstrate here that despite the in vitro similarities between LY354740 and LY404039, oral administration of LY404039 results in much higher plasma levels and bioavailability (63%; Monn et al, 2007) than previously observed following oral administration of LY354740 (ϳ10%; Johnson et al, 2002) and a different pharmacokinetic profile. The mechanism by which LY404039 crosses the gastrointestinal tract is not clearly understood.…”

“…Interestingly, although similar to LY354740, LY404039 was ϳ2-to 3-fold less potent in this assay. Despite the slightly lower potency of LY404039 versus LY354740 in binding and functional assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments in rats [ϳ63% (see Monn et al, 2007) compared with ϳ10% for LY354740 (Johnson et al, 2002)]. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, an effect reversed by the mGlu2/3 receptor antagonist LY341495, indicating that the suppression of neural activity was probably mediated via mGlu2/3 receptors.…”

“…Importantly, LY354740 was well tolerated in those studies. However, the clinical development of LY354740 has been hampered by low oral bioavailability, due to minimal absorption in the gastrointestinal tract and inadequate penetration through the blood-brain barrier (Johnson et al, 2002;Bueno et al, 2005). Although recent attempts to improve the oral bioavailability of this compound have met with good success (Rorick-Kehn et al, 2006), further research has been devoted to discovering additional potent and selective mGlu2/3 receptor agonists.…”