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 [betaAla8]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 [betaAla8]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 [betaAla8]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.