vasoactive-intestinal-peptide and difenoxin

The opiate antidiarrhoeal drugs loperamide (0.6 mg kg-1, i.p.) or difenoxin (0.77 mg kg-1, s.c.), were administered in an anaesthetic mixture (pentobarbitone 60 mg kg-1) to rats. A length of jejunum (approx. 30 cm) was cannulated, washed and then perfused with iso-osmotic saline for 20 min. The perfusion commenced 50 min after drug administration and continued for 20 min. The perfusates were collected for analysis of fluid transport rates and antidiarrhoeal drug content. These doses of the antidiarrhoeals caused marked inhibition of intestinal fluid secretion induced by intra-arterial infusion of vasoactive intestinal peptide. However, neither of the antidiarrhoeal drugs were detected in the intestinal perfusates (< 0.5 ng by HPLC). The results indicate that loperamide and difenoxin have a different pharmacokinetic profile compared with that previously found for morphine under the same conditions.

Topics: Absorption; Animals; Antidiarrheals; Calibration; Castor Oil; Chromatography; Diarrhea; Diphenoxylate; Female; Intestinal Mucosa; Intestinal Secretions; Loperamide; Male; Narcotics; Rats; Rats, Wistar; Vasoactive Intestinal Peptide

Experiments have been performed to determine whether the antisecretory (antidiarrhoeal) actions of difenoxin and loperamide are mediated by enteric neurones. An iso-osmotic perfusion solution was circulated around the lumen of the jejunum of anaesthetised rats. Vasoactive intestinal peptide was infused intra-arterially to induce net fluid secretion which was inhibited by difenoxin (ED50, 0.23 mg/kg) and loperamide (ED50, 0.5 mg/kg). However, neither were able to restore the fluid transport rate to the control level of absorption. The antisecretory effects of difenoxin (0.77 mg/kg) and loperamide (0.6 mg/kg) were blocked by the opiate receptor antagonist naloxone (2 mg/kg). Their effects were also abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA; 200 mg/kg; with desmethylimipramine given beforehand to protect noradrenergic nerves and enhance 5-HT depletion). The effect of difenoxin was blocked with methiothepin (1 mg/kg) and methysergide (30 micrograms/kg) but not ketanserin (30 micrograms/kg), ritanserin (30 mg/kg), ondansetron (10 micrograms/kg) or ICS 205-930 (3 mg/kg). None of the above 5-HT receptor antagonists modified the antisecretory effect of loperamide. The antisecretory effect of difenoxin but not loperamide was prevented by phentolamine (2 mg/kg) and by pretreatment with 6-hydroxy-dopamine (150 mg/kg total). It is concluded that both difenoxin and loperamide inhibit net fluid secretion by indirect mechanisms. It is proposed that the initial action is on enteric mu-opiate receptors and that this results in the release of 5-HT. In the case of difenoxin, the 5-HT may act on 5-HT1-like receptors to release noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antidiarrheals; Diphenoxylate; Dose-Response Relationship, Drug; Drug Interactions; Female; Intestinal Absorption; Jejunum; Loperamide; Male; Models, Biological; Morphine; Narcotic Antagonists; Rats; Rats, Wistar; Receptors, Opioid; Serotonin; Serotonin Antagonists; Vasoactive Intestinal Peptide