Received for publication April 11, 2007.
Revised July 12, 2007.
Accepted for publication July 19, 2007.

Pharmacokinetics, Metabolism, and Excretion of the PepT1-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

Abstract

The peptidyl prodrug (1S,2S,5R,6S)-2-[(2'S)-(2-Amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid, also known as LY544344, was discovered to improve the oral bioavailability of the parent drug LY354740, a potent group II metabotropic glutamate receptor agonist. This prodrug has been shown to deliver high plasma concentrations of the active drug via PepT1-mediated intestinal transport and presystemic hydrolysis in preclinical species. The current data describe the pharmacokinetic behavior of LY544344 and LY354740, with a specific focus on the first-pass activation processes and dose-linearity in rats and dogs. The PepT1 transporter makes an attractive prodrug target because of its high capacity and relatively broad substrate specificity. This was demonstrated by the wide dose-proportionality observed in both species (up to 1000 mg/kg in rat and 140 mg/kg in dogs). Following oral administration of LY544344, absorption and bioactivation was extensive and rapid, with greater than 97% of prodrug hydrolysis occurring prior to appearance in the hepatic portal vein. Systemic activation was likewise extensive, with 100% conversion of a 7 mg/kg intravenous dose in dogs. Radiolabeled studies confirmed that hydrolysis to LY354740 was the only metabolic pathway and that the excretion pattern of the active drug was not altered by administration of the prodrug. These results demonstrate the nearly ideal prodrug properties of LY544344 and further validate the utility of the peptide transporter-directed approach to prodrug design.

Key words: drug absorption, drug disposition, intestinal bioavailability, prodrugs, targeted delivery, transporters