Vol. 299, Issue 1, 247-254, October 2001

Nepadutant Pharmacokinetics and Dose-Effect Relationships as Tachykinin NK₂ Receptor Antagonist Are Altered by Intestinal Inflammation in Rodent Models

Alessandro Lecci, Francesca Carini, Manuela Tramontana, Vincenzo D'Aranno, Erica Marinoni, Attilio Crea, Lionel Bueno, Jean Fioramonti, Marco Criscuoli, Sandro Giuliani and Carlo Alberto Maggi

Pharmacology Department, Menarini Ricerche, Firenze, Italy (A.L., F.C., M.T., M.C., S.G., C.A.M.); Pharmacokinetics and Metabolism Department, Menarini Ricerche, Pomezia Roma, Italy (V.D., E.M., A.C.); and Pharmacology and Toxicology Department, Institut National de la Recherche Agronomique, Toulouse, France (L.B., J.F.)

Tachykinin NK₂ receptor antagonists could reduce motility and symptoms during gastrointestinal diseases characterized by local inflammation such as diarrhea or colitis; however, how these conditions change pharmacodynamic and pharmacokinetic characteristics of NK₂ receptor antagonists is unknown. We investigated the effect of the peptide NK₂ receptor antagonist nepadutant on spontaneous intestinal motility or [Ala⁸]NKA(4-10)-induced colonic and bladder contractions in rodent models of intestinal inflammation (enteritis induced by castor oil and rectocolitis induced by local instillation of acetic acid in rats, enteritis induced by bacterial toxins in mice). In the castor oil model, the oral/intraduodenal bioavailability of nepadutant was also determined. The intrarectal (i.r.) administration of nepadutant (100 nmol/kg) did not reduce [Ala⁸]NKA(4-10) (10 nmol/kg i.v.)-induced colonic and bladder contractions in normal animals, but the same dose of nepadutant produced an inhibitory effect in the two organs following rectocolitis; in contrast, nepadutant is equieffective by the intravenous route in normal and colitic animals. In this model, nepadutant (100 nmol/kg i.r. or i.v.) decreased spontaneous colonic hypermotility, without affecting motility in controls. The intraduodenal administration of nepadutant (30 nmol/kg), which was ineffective on [Ala⁸]NKA(4-10) (10 nmol/kg i.v.)-induced colonic and bladder contractions in control animals, abolished bladder contractions in castor oil-pretreated animals. In this latter group, the oral and intraduodenal bioavailability of nepadutant showed a 7- to 9-fold increase with respect to controls. Oral administration of nepadutant, in nanomolar or subnanomolar dosage, reduced diarrhea induced by bacterial toxins in mice. It is concluded that intestinal inflammation increases nepadutant absorption in the intestine, enhancing its activity. These results suggest that a drug with a limited oral bioavailability could be used for treating gastrointestinal diseases associated with a local inflammation.