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PubMed2004

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion.

1. Transporters have been increasingly identified as a factor in limiting the oral bioavailability of certain drugs. Previously, the present authors investigated a compound (SB-265123) with an apparent absolute oral bioavailability (Fapp) consistently > 100%, and excluded likely artefactual causes for this observation, as well as standard considerations of non-stationary or non-linear pharmacokinetics. The data led the authors to believe that SB-265123 might be a transporter substrate in the rat, and it was hypothesized that transporter interactions might be responsible for the observed Fapp > 100%. 2. In the present study, a model was proposed incorporating rapid and complete absorption and elimination by a saturable intestinal secretory pathway. Intestinal secretion was demonstrated for SB-265123 using a rat single-pass intestinal perfusion technique. In addition, in a study employing both independent and simultaneous intravenous and oral administration of SB-265123, exposure to SB-265123 was greater than additive on joint intravenous and oral administration, lending further support to the hypothesis of a saturable transporter. Furthermore, in a study with co-administration of GF120918A, a transporter inhibitor, the observed Fapp for SB-265123 was only 84 +/- 17%, providing additional evidence for transporter involvement in the >100% Fapp phenomenon. 3. Experience with SB-265123 illustrates a counterintuitive impact of transporters on oral bioavailability and highlights the importance of considering transporter interactions in the systemic disposition of xenobiotics, even those not demonstrating low oral bioavailability.

Acetates↗
PubMed2004

Intracellular potentiation between two second messenger systems may contribute to cholera toxin induced intestinal secretion in humans.

BACKGROUND: Cholera toxin (CT) acts on intestinal epithelial cells both directly and indirectly via activation of a secretory neural reflex. The reflex may release acetylcholine as one of its final neurotransmitters. This opens up the possibility of a third mechanism of action for CT, namely a synergistic interaction between two secretagogues acting on different second messenger systems within the epithelial cell. AIMS: To establish evidence for cholinergic innervation to human ileal epithelial cells and to investigate whether CT potentiates the action of acetylcholine on human intestinal epithelial cells. METHODS: Transverse sections of human ileum were examined for mucosal cholinergic nerves and M3 muscarinic receptors using antibodies raised to choline acetyltransferase and M3 receptors. Short circuit current (Isc) responses and ion flux movements were elicited from T84 epithelial cell monolayers set up in Ussing chambers. RESULTS: Immunohistochemistry of native human ileal mucosa revealed the presence of both cholinergic nerves and muscarinic M3 receptors located to the basolateral domain of epithelial cells. Secretory responses of T84 cell monolayers to acetylcholine were greatly potentiated in the presence of CT. This effect, substituting forskolin for CT, was mirrored by increases in basolateral 86Rb and apical 125I efflux. Charybdotoxin plus apamin reduced both Isc and 86Rb efflux evoked by acetylcholine, in the presence of forskolin. CONCLUSIONS: Human ileal mucosa receives a direct cholinergic innervation to its epithelial cells. Secretory effects of acetylcholine on epithelial cells are augmented in the presence of CT. Such a synergistic response is dependent on optimum opening of basolateral potassium channels by acetylcholine and apical chloride channels by CT. The interaction may contribute to the mechanism of action of cholera toxin induced secretory diarrhoea.

Acetylcholine↗
PubMed1989

Diarrhoea in jaundiced neonates treated with phototherapy: role of intestinal secretion.

Thirty jaundiced neonates with diarrhoea who were being treated with phototherapy and 30 matched control infants were studied to try and find out the cause of the diarrhoea. Faecal osmolality and electrolyte concentrations were measured, which gave clear evidence that the diarrhoea arose from intestinal secretion. Rectal water and electrolyte absorption in 10 jaundiced infants receiving phototherapy, in 10 jaundiced infants not receiving phototherapy, and in 10 healthy controls was measured with a rectal dialysis bag. A further group of eight jaundiced infants was also studied both during and after phototherapy to document the reversal of ion transport changes. Absorption of water, sodium chloride, and potassium was significantly impaired in the patients receiving phototherapy compared with each of the control groups. Such impairment was transient, as it was not apparent when the jaundice faded and phototherapy was stopped. These data show that the colon plays a part in the pathogenesis of secretory diarrhoea and that both hyperbilirubinaemia and phototherapy are necessary for such an effect to develop.

Diarrhea, Infantile↗
PubMed1978

Effects of intraluminal glucose on intestinal secretion induced by heat stable and heat labile Escherichia coli enterotoxin, cholera toxin and theophylline.

Glucose, l-alanine, l-aspartate, l-methionine and glycine enhanced net fluid and electrolyte absorption in acute isolated loops of the proximal jejunum of weanling swine. The effect of glucose on intestinal secretion induced by heat stable and heat labile Escherichia coli entero-toxin, cholera toxin and theophylline was examined in both the proximal and distal jejunum of weanling swine. In the proximal jejunum glucose enhanced the rate of net fluid and electrolyte absorption. This increase was accompanied by an increase in unidirectional dosium absorption. In loops exposed to either heat stable or heat labile enterotoxins, glucose significantly decreased the rate of net fluid and electrolyte secretion. The magnitude of glucose enhancement in loops exposed to heat stable and heat labile enterotoxins was similar to adjacent control loops. However, glucose enhancement did not occur in loops exposed previously to cholera toxin or concurrently to theophylline. Therefore, cholera toxin and theophylline may inhibit substrate dependent sodium absorption in the proximal jejunum. In the distal jejunum glucose enhancement did occur but the rate of enhancement was less than in the proximal jejunum. In this region glucose enhancement was not evident in loops exposed to either theophylline, heat stable, heat labile or cholera toxin.

Amino Acids↗
PubMed2003

Cholera toxin protects against action by Clostridium difficile toxin A. The role of antisecretory factor in intestinal secretion and inflammation in rat.

UNLABELLED: The protein antisecretory factor (AF) inhibits intestinal fluid secretion induced by the cholera toxin (CT) and Clostridium difficile toxin A (CDA). The present work investigated whether CT-induced AF protects against the enterotoxin action by CDA. Rats were pretreated perorally with CT or buffer as control, whereafter CDA-induced fluid secretion and cytotoxicity was tested in vivo in ligated intestinal loops; the mucosal level of AF was estimated using the Western blot technique. Rats given repeated peroral doses of CT became tolerant to CDA, the inhibition of fluid secretion and of cytotoxicity being 79% in eight out of nine animals. The repeated CT-treatment also induced long-lasting rise of AF in the mucosal epithelium. Recombinant AF given either perorally or intravenously inhibited both fluid secretion and cytotoxicity by CDA; similar results were obtained with a truncated 16-mer AF peptide. IN CONCLUSION: peroral CT-treatment induced tolerance to CDA in rat small intestine. The tolerance was probably mediated by AF induced via action of cholera toxin on the enteric nervous and immune system.

Animals↗
PubMed1989

Inhibition of cholera toxin-induced intestinal secretion by the 5-HT3 receptor antagonist ICS 205-930.

The secretory effect of cholera toxin on the gut has been ascribed to the activation of submucosal 5-hydroxytryptamine receptors by 5-hydroxytryptamine released from the enterochromaffin cells. The hypothesis that neuronally located 5-HT3 receptors are involved in cholera toxin-induced diarrhoea has now been tested. Intestinal secretion was stimulated in mice by oral administration of pure cholera toxin and the effects of ICS 205-930, a potent and selective antagonist at 5-HT3 receptors, and of ketanserin, a compound that blocks 5-HT2 receptors, were investigated. Oral administration of cholera toxin resulted in a significant accumulation of fluid in the intestine. Pretreatment of the animals with ICS 205-930 partly prevented this effect and a maximal reduction of about 50% was achieved with doses of 0.3 mg/kg i.p. and higher. Ketanserin had only minimal effects up to a high dose of 1 mg/kg i.p. when a 20% reduction of fluid accumulation was seen. The data support the view that activation of 5-HT3 receptors plays a major role in the secretory effect of cholera toxin in the gut.

Animals↗
PubMed1974

Reversal of cyclic AMP-mediated intestinal secretion by ethacrynic acid.

Ethacrynic acid (EA) has been reported to reduce cholera toxin-induced intestinal fluid secretion in the intact animal. We explored the nature of this inhibition in vitro by measuring unidirectional, transmural fluxes of (22)Na and (36)Cl across isolated rabbit ileal mucosa. Under control conditions (short-circuited mucosa bathed in bicarbonate-Ringer), there was net absorption of Na and Cl. Theophylline (10 mM), cyclic AMP (5 mM), and cholera toxin (added in vivo) abolished net Na flux and produced net Cl secretion. In the presence of either theophylline or cAMP, addition of 0.1 mM EA to the serosal bathing solution abolished net Cl secretion and restored net Na absorption. Cholera toxin-treated mucosa was exposed to 0.05 and 1.0 mM EA. The lower concentration restored net Na absorption but did not significantly reduce Cl secretion. The higher concentration abolished net transport of both Na and Cl. Short-circuit current and Na flux measurements in the presence and absence of glucose indicated that 0.1 mM EA does not inhibit glucose-coupled Na transport. Short-circuit current measurements in the presence of 1.0 mM EA suggested that even this concentration of EA does not inhibit glucose-coupled Na transport. Thus EA appears to specifically inhibit Cl (or NaCl) secretion without inhibiting the absorptive Na "pump." The anti-secretory effect of 0.1 mM EA does not appear to result from inhibition of adenylate cyclase since secretion stimulated by addition of 5 mM cAMP was abolished. Furthermore, 0.1 mM EA did not significantly reduce theophylline-augmented and cholera toxin-augmented cAMP levels in ileal mucosa. We conclude that EA interacts specifically with the active Cl (or NaCl) secretory mechanism of the small intestine at a step beyond generation of cAMP.

Animals↗
PubMed1974

Intestinal secretion.

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Adrenergic beta-Antagonists↗
PubMed1981

Immune responses of rats to live Vibrio cholerae: antibodies in serum and intestinal secretions.

Following injection of live Vibrio cholerae into the small intestine of rats, antibodies appear in the serum and mucus secretions associated with the intestinal surfaces. In contrast to oral immunization, single pulses given by this route cause primary and secondary agglutinating and vibriocidal antibody responses; they are slower to develop but similar to those induced by intravenous injection of 10-fold lower doses of the organisms. However, the intestinal route of injection appears to favour local formation of agglutinating antibodies that are directly transferred to the mucus secretions; it is likely that these are of the sIgA class. Evidence has also been presented which suggests that intestinal injection causes formation of antibodies which inhibit agglutination of V. cholerae by type-specific antiserum; these inhibitory effects are eliminated if the reaction is carried out in the presence of diluted normal rabbit serum rather than saline.

Animals↗
PubMed2000

Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction.

BACKGROUND: P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate talinolol, a beta1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings. METHODS: Pharmacokinetics of talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1-messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years). RESULTS: During rifampin treatment, the areas under the curve of intravenous and oral talinolol were significantly lower (21% and 35%; P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous talinolol (rs = 0.74; P < .001). CONCLUSIONS: Rifampin induces P-glycoprotein-mediated excretion of talinolol predominantly in the gut wall. Moreover, clearance of talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1981

Identification and origins of neutral fecal sterols in adult Large White sows: occurrence of externally-secreted intestinal cholesterol.

Cholesterol, the main neutral fecal sterol (54-84 p. 100) in adult Large White sows fed a controlled semi-purified diet containing 0.08 p. 100 cholesterol (500 g twice a day; 3 510 kcal/day), was partially converted into coprostanol (10-44 p. 100). Exceptionally, epicoprostanol was present, indicating a second pathway of bacterial cholesterol degradation. In this paper, the term "fecal cholesterol" is restricted to the sum of cholesterol + coprostanol. The contribution of fecal cholesterol to the bulk of neutral fecal sterols eliminated daily, averaged 97 +/- 1 p. 100. For a given dietary cholesterol intake of 80 mg per day, eliminated fecal cholesterol was estimated to be 392 +/- 47 mg/day and mean fecal cholesterol concentration 1.88 +/- 0.12 mg/g of stools. The various sources of fecal cholesterol were unabsorbed ingested cholesterol, cholesterol excreted from the plasma, and externally-secreted intestinal cholesterol, synthesized by the digestive tract, discharged into the lumen and not absorbed. The respective contributions of these different sources were as follows: unabsorbed dietary cholesterol 34 +/- 2 mg/day, excreted cholesterol 234 +/- 28 mg/day and externally-secreted cholesterol 125 +/- 23 mg/day.

Animals↗