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

Abstract

ABSTRACT:The peptidyl prodrug (1S,2S,5R,6S)-2-[(2S)-(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 (؉)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a potent group II metabotropic glutamate receptor agonist. This prodrug has been shown to deliver high plasma concentrations of the active drug via intestinal peptide transporter 1 (SLC15A1) (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 rats and 140 mg/kg in dogs). After oral administration of LY544344, absorption and bioactivation were extensive and rapid, with greater than 97% of prodrug hydrolysis occurring before its 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.

Transepithelial Transport of the Group II Metabotropic Glutamate 2/3 Receptor Agonist (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740) and Its Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY544344)

“…The saturable activity of the peptidase(s) was substantiated with the evidence that negligible LY544344 was detected in the cells at low concentrations and that the cellular accumulation ratio of LY354740/LY544344 decreased as the apical LY544344 concentration increased. Recent oral pharmacokinetic studies in rats and dogs showed evidence of saturation of the absorption process at high doses (Perkins and Abraham, 2007).…”

“…Earlier GlySar uptake studies in cell culture models and oral pharmacokinetic studies in rats and dogs indicated that LY544344 had affinity to the intestinal peptide transporter, PEPT1, and was extensively biotransformed into the active moiety, LY354740, before reaching the systemic circulation (Bueno et al, 2005;Rorick-Kehn et al, 2006;Perkins and Abraham, 2007). Bueno et al (2005) reported IC 50 values of 0.30 and 0.12 mM for LY544344 in the GlySar uptake inhibition studies using the Caco-2 and human PEPT1-transfected Chinese hamster ovary cell lines, respectively, suggesting a strong affinity to PEPT1.…”

“…1) (Bueno et al, 2003(Bueno et al, , 2005. LY544344 is metabolized to release LY354740 by both human jejunal homogenates and rat liver homogenates (Bueno et al, 2005) and is almost completely converted to LY354740 after oral dosing of LY544344 to rats and after oral or intravenous dosing to dogs (Perkins and Abraham, 2007). Furthermore, the bioavailability of LY354740 after oral administration of LY544344 was increased from 10 to 84% in rats, suggesting that LY544344 might be a suitable prodrug for LY354740 in humans (Bueno et al, 2005).…”

Oral Absorption: from Physiology to Regulatory

“…Perkins and Abraham, at Eli Lilly, put in practice this approach and delivered the prodrug LY544344, demonstrating the utility of PepT1-targeted nonester prodrugs to overcome poor permeability and low bioavailability. This compound exhibits near-ideal prodrug properties, with good solubility and chemical stability, extensive and reproducible absorption across species, low concentrations of circulating nontoxic prodrug, and pharmacokinetic linearity across a wide dose range [73].…”

Synthesis and Biopharmaceutical Studies of JLTN as Potential Dasatinib Prodrug

“…Therefore, it is necessary to increase the absorption rate of Dasatinib as well to decrease the rate of its metabolism. [9][10][11][12] In this current study, a series of amino acid derivatives (see Fig. 2, 144 compounds) as potential prodrugs of Dasatinib were designed with the aim of improving aqueous solubility and therapeutic efficacy, in terms of use of computer-aided drug design methodologies (small molecule flexible docking, virtual screening, three dimensions (3D) database search, lead optimization, 3D-quantitative structure-activity relationship (3D-QSAR), pharmacophore generation and peptide transporter).…”