PHARMACOKINETICS OF THE BICYCLIC PEPTIDE TACHYKININ NK2 RECEPTOR ANTAGONIST MEN-11420 (NEPADUTANT) IN RATS

The pharmacokinetics of MEN 11420 [nepadutant, c[[(beta-D-GlcNAc)Asn-A sp-Trp-Phe-Dpr-Leu]c(2 beta-5 beta)]], a potent glycosylated analogue of the selective, bicyclic peptide, tachykinin NK, receptor antagonist MEN 10627 [c[(Met-Asp-Trp-Phe-Dpr-Leu)c(2 beta-5 beta)]], were studie d in rats after different routes of administration. The plasma concent ration profile for MEN 11420 after iv administration (1 mg/kg) was com pared with that for the parent compound MEN 10627. The mean plasma hal f-life (44 min) and AUC value (285 mu g.min/ml) for MEN 11420 were alm ost 3-fold greater than those for MEN 10627, and the systemic clearanc e was reduced to one third. The absolute bioavailabitity of MEN 11420 after intranasal (1 mg/kg) or ip (1 mg/kg) administration was virtuall y complete. However, bioavailability was only approximately 5% after i ntrarectal 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 excr etion of unchanged compound, after an iv dose of 1 mg/kg, was approxim ately 34% of the dose for MEN 11420 but was < 2% for MEN 10627. This i s in agreement with in vitro data showing that MEN 11420 is more resis tant to hydrolytic and oxidative metabolism than is MEN 10627, It is c oncluded that the hydrophilic modification of MEN 10627 to produce MEN 11420 resulted in marked improvement in the pharmacokinetic and metab olic characteristics of the peptide.