Abstract

The pharmacokinetics of MEN 11420 [nepadutant, c[[(β-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2β-5β)]], a potent glycosylated analogue of the selective, bicyclic peptide, tachykinin NK₂ receptor antagonist MEN 10627 [c[(Met-Asp-Trp-Phe-Dpr-Leu)c(2β-5β)]], were studied in rats after different routes of administration. The plasma concentration profile for MEN 11420 after iv administration (1 mg/kg) was compared with that for the parent compound MEN 10627. The mean plasma half-life (44 min) and AUC value (285 μg·min/ml) for MEN 11420 were almost 3-fold greater than those for MEN 10627, and the systemic clearance was reduced to one third. The absolute bioavailability of MEN 11420 after intranasal (1 mg/kg) or ip (1 mg/kg) administration was virtually complete. However, bioavailability was only approximately 5% after intrarectal treatment (5 mg/kg) and was too low to be quantified (<3%) after sublingual (1 mg/kg) or oral (10 mg/kg) doses. The urinary excretion of unchanged compound, after an iv dose of 1 mg/kg, was approximately 34% of the dose for MEN 11420 but was <2% for MEN 10627. This is in agreement with in vitro data showing that MEN 11420 is more resistant to hydrolytic and oxidative metabolism than is MEN 10627. It is concluded that the hydrophilic modification of MEN 10627 to produce MEN 11420 resulted in marked improvement in the pharmacokinetic and metabolic characteristics of the peptide.