Acceleration of large intestine transit time in rats by sennosides and related compounds

Sennosides A + B and their natural metabolites, sennidins A + B, rheinanthrone and rhein, as well as the synthetic laxative danthron, were investigated for their influence on small and large intestine transit time in rats. Carmine red, as a marker, was administered through a gastric tube for small intestine transit or intracaecally by a chronically implanted catheter for colon transit. High doses of sennosides (250-500 mg kg-1) given orally from 20 min or up to 6 h before marker administration had no effect on small intestine transit time. The metabolites and danthron (10-100 mg kg-1 p.o.) also did not accelerate upper gastrointestinal passage. Intracaecal administration at the same time as carmine red, however, reduced the time for the appearance of the first coloured faeces from more than 8 h in the controls to 46 +/- 9 min after sennosides, 34 +/- 11 min after sennidins, 53 +/- 83 min after rhein and 16 +/- 4 min after rheinanthrone (50 mg kg-1 of each). Danthron was ineffective. Thus, sennosides and their natural metabolites specifically influence large intestinal motility. Acceleration of colonic transport seems to be a major component of the laxative action whereas for danthron motility changes are not responsible for its laxative action. Indomethacin partly inhibited the acceleration of large intestine transit induced by sennosides. An involvement of endogenous prostaglandins may therefore be possible, although a local bolus administration of PGF2 alpha or PGE2 into the caecal lumen neither influenced transit time nor induced diarrhoea.     

Effects of sennosides A + B and bisacodyl on rat large intestine

Oral and intracecal administration of bisacodyl or sennosides A + B (10-100 mg/kg each) to rats induced a similar quantity of soft feces within 24 h and a similar acceleration of large intestinal transit time, but in each case bisacodyl had a prolonged action. Net fluid absorption in the perfused rat colon was reduced to a comparable extent by local bisacodyl in 1/10 of the molar concentration of rhein, an active metabolite of sennosides; recovery was delayed after bisacodyl. These results show that the time course of the laxative action of both drugs is different, probably attributable to their different pharmacokinetics. Both drugs influence colon motility as well as colonic secretion, but fluid secretion may contribute more to the laxative effect of bisacodyl than to that of sennosides.     

Effect of anthraquinone derivatives on canine and rat intestinal motility

The effects on gastrointestinal motility of 3 senna preparations containing 18% oxidized Ca-sennosides, 60% Ca-sennosides, or pure sennosides A + B were tested in dogs and rats as measured by electromyography. Oral administration of the oxidized products in the fasted animal increased the activity of the small intestine within 2 h and reduced both caecal and colonic contractions for 24 h. Severe diarrhoea was present 4-6 h after administration and lasted for at least 1 day. Ca-sennosides had a similar, but weaker effect while pure sennosides affected motility only 6-10 h after oral administration. The intracolonic administration of the oxidized products resulted in an immediate reduction of colon motility for 7-8 h and diarrhoea was present within 40 min. Intracolonic Ca-sennosides and sennosides A + B induced only small changes in the intestinal motility, but diarrhoea also appeared. The results confirm that pure sennosides act predominantly on large intestine motility after their degradation by colonic microorganisms. Oxidized products are already effective in the upper gastrointestinal tract. The early action of Ca-sennosides requires further investigation. Side effects after oral senna treatment such as griping or nausea may be caused by motility changes induced by the presence of small amounts of oxidized products in the drug.     

Effect of anthraquinone derivatives on canine and rat intestinal motility

The effects on gastrointestinal motility of 3 senna preparations containing 18% oxidized Ca-sennosides, 60% Ca-sennosides, or pure sennosides A + B were tested in dogs and rats as measured by electromyography. Oral administration of the oxidized products in the fasted animal increased the activity of the small intestine within 2 h and reduced both caecal and colonic contractions for 24 h. Severe diarrhoea was present 4–6 h after administration and lasted for at least 1 day. Ca-sennosides had a similar, but weaker effect while pure sennosides affected motility only 6–10 h after oral administration. The intracolonic administration of the oxidized products resulted in an immediate reduction of colon motility for 7–8 h and diarrhoea was present within 40 min. Intracolonic Ca-sennosides and sennosides A + B induced only small changes in the intestinal motility, but diarrhoea also appeared. The results confirm that pure sennosides act predominantly on large intestine motility after their degradation by colonic microorganisms. Oxidized products are already effective in the upper gastrointestinal tract. The early action of Ca-sennosides requires further investigation. Side effects after oral senna treatment such as griping or nausea may be caused by motility changes induced by the presence of small amounts of oxidized products in the drug.     

Prostaglandin E2-mediated stimulation of mucus synthesis and secretion by rhein anthrone, the active metabolite of sennosides A and B, in the mouse colon

Rhein anthrone, the active metabolite of sennosides A and B, stimulated PGE2 release into the mouse colonic lumen. At 6.24 mg kg-1, it decreased net water and Na+ absorption significantly in the case of water, but could not reverse the net absorption in mouse ligated colon, although it enhanced net K+ secretion. Pretreatment with indomethacin diminished the effects of rhein anthrone except on K+ net secretion. Rhein anthrone or PGE2 markedly stimulated mucus secretion and synthesis in mouse ligated colon. The enhanced mucus secretion and synthesis induced by rhein anthrone were significantly suppressed by pretreatment with indomethacin. Our results have shown that the colonic secretion of water and electrolytes mediated by PGE2 is partly involved in the rhein anthrone-induced diarrhoea but that in mice, the mucoid diarrhoea induced by rhein anthrone results mainly from PGE2-mediated mucus synthesis and secretion in the colon.     

Stimulation of PGE2 synthesis and water and electrolyte secretion by senna anthraquinones is inhibited by indomethacin

The effect of dried senna pod extract, containing 10% sennoside B, on colonic electrolyte and fluid transport was examined in the anaesthetized rat in-situ. Oral administration of senna pod extract dose-dependently (17.5-30 mg kg-1, calculated as sennoside B) reversed net absorption of water, sodium and chloride to net secretion and increased potassium secretion. Senna pod extract stimulated the output of prostaglandin E2 into the colonic lumen. Inhibition of prostaglandin biosynthesis by pretreatment of the rats with indomethacin (10 mg kg-1) significantly inhibited the effects of senna pod extract (17.5-30 mg kg-1) both on net fluid transport and on prostaglandin E2 synthesis. The inhibitory effect of indomethacin on net fluid transport induced by senna pod extract (30 mg kg-1) was dose-dependent. It is concluded that anthraquinones exert their laxative action at least partially via stimulation of colonic fluid and electrolyte secretion, and that this secretion is mediated by stimulation of endogenous prostaglandin E2 formation.     

Comparison of the antisecretory effects of loperamide and loperamide oxide in the jejunum and the colon of rats in-vivo

The antidiarrhoeal effect of loperamide is caused by its antimotility and antisecretory properties. In-vivo experiments in the rat jejunum and colon have been performed to compare the antisecretory effect of loperamide with the effect of its prodrug, loperamide oxide. Both loperamide and loperamide oxide administered intraluminally, equally and dose dependently (2 to 250 micrograms mL-1) reduced PGE2-induced net fluid secretion (32 ng min-1 i.a.) in the jejunum and colon. The antisecretory effect of both drugs is blocked by naloxone (1 mg kg-1 s.c.). It is concluded that loperamide oxide administered intraluminally is reduced to loperamide and has the same antisecretory potency as loperamide in jejunum and colon. The effect appears to be mediated via opiate receptors. The observation that loperamide cannot be detected in the colonic lumen two h after oral administration suggests that the drug is delivered from the blood stream to the site of action after absorption in the small intestine.     

Physiology of the colorectal barrier

The colon is a suitable site for the safe and slow absorption of drugs which are targetted at the large intestine or designed to act sytemically. The physiology of the colorectal barrier is complex and influenced by many factors including diet, bacterial metabolism and colonic mixing and transit time. As the motility and absorption characteristics of the colon change from the proximal colon to the rectum, the physiology of these regions and the likely residence time of any drug at each site must be understood for the full potential of the colon to be exploited. This article will discuss the main physiological factors affecting the colon and hence colonic drug absorption.     

Sennoside-induced Secretion is Not Caused by Changes in Mucosal Permeability or Na+,K+-ATPase Activity

Abstract— The effect of sennosides (50 mg kg^?1) on the rat colon in-situ was studied 6 h after oral treatment when the laxative effect was maximal. In a second experiment, rhein (4 × 10^?3 m ), an active sennoside metabolite, was administered into the lumen of the colon for 1 h. Both sennosides and rhein reduced net H₂O and Na⁺ absorption or reversed it to net secretion. Paracellular permeability, as measured using erythritol as a small marker molecule, was increased 2- to 3-fold; permeability to a large molecule, PEG 1000, was unchanged. The activity of Na⁺, K⁺-ATPase in the colon mucosa was not affected. There was no damage of the epithelial cells as determined by lactic acid dehydrogenase release. These results indicate that neither inhibition of Na⁺, K⁺-ATPase nor damage of the colon epithelium are involved in the secretory effect of sennosides or rhein. The increased paracellular permeability of small molecules fits into the concept of stimulation of active chloride secretion by sennosides, which is electrochemically and osmotically balanced by an increase in Na⁺ and H₂O flow via the paracellular pathway.     

The involvement of opiate receptors in the effects of trimebutine on intestinal motility in the conscious dog

The effects of intravenous (i.v.) vs intracerebroventricular (i.c.v.) administration of trimebutine on the motility of the small intestine and colon of fasted dogs were assessed using chronic electromyography. Trimebutine, injected intravenously, stimulated small intestinal motility, by inducing a propagated phase of regular spike activity, and inhibited colonic motility for some 4 h. These effects were not reproduced by i.c.v. administration which disrupted the cyclic motor profile of the small intestine for about 2.5 h and did not modify colonic motility. The stimulation of the small intestine motility induced by i.v. administration of the drug was blocked by previous i.v. but not by i.c.v. administration of naloxone. It was concluded that in the dog, the effects of trimebutine on the small intestine but not on the colon, involve peripheral opiate receptors.     

Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy.

1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration-time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/- 0.4 h, mean +/- s.d.), and the time to arrival in the colon (3.8 +/- 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/- 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration-time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear.     

Effect of altered gastric emptying and gastrointestinal motility on metformin absorption

AIMS: The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects. METHODS: An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99mTc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic findings. RESULTS: Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,infinity) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma profile always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival. CONCLUSIONS: Metformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These findings have significant implications in the design of a metformin modified release dosage form.     

Inhibition of intestinal water and electrolyte absorption by senna derivatives in rats

Three intestinal segments were simultaneously perfused with Tyrode solution in the anaesthetized rat using a perfusion rate of 12 ml h^?1. Dried purified senna extract containing 60% Ca-sennosides A + B (I) administered with the perfusion fluid had no or only minimal effects on intestinal absorption. Large doses (4 g litre^?1) slightly reduced net Na, CI and H₂O absorption predominantly in the colon and the ileum; the jejunum was unaffected. Dried purified senna extract containing 18% oxidized Ca-sennosides (II) reduced net Na, Cl and H₂O absorption in all three intestinal segments, the effects increasing from the jejunum to the colon. Large doses (4 g litre^?1) induced net Na and H₂O secretion. II being administered with the colon perfusion fluid affected H₂O and electrolyte absorption in the colon and to a lesser degree, in the ileum. Pure rhein (III, 0·28 g litre^?1) had similar effects to II. Pure sennosides A + B (IV, 2 g litre^?1) had no effect on intestinal absorption. These results confirm that changes in the absorptive behaviour of the gut mucosa are, at least partly, responsible for the laxative action of anthraquinone drugs and that this effect is mainly dependent on the presence of oxidized derivatives. There is evidence that the drug's effect is not locally restricted to the colon as is seen from the ileal response after intracolonic administration. Side-effects like griping which are sometimes observed after senna treatment seem to originate from motility changes rather than from changes in absorption.     

Suppression of the purgative action of rhein anthrone, the active metabolite of sennosides A and B, by indomethacin in rats.

Rhein anthrone (12.48 mg kg-1) produces watery and mucoid diarrhoea approximately 20 min after intracaecal administration to rats. Pretreatment with the prostaglandin (PG) biosynthesis inhibitor indomethacin (10 mg kg-1, i.p.) only delayed and did not completely block the onset of the induced diarrhoea. Rhein anthrone stimulated PGE2 release into the rat colonic lumen and the increased release was depressed by indomethacin. Rhein anthrone also accelerated large intestinal transit and this acceleration could be partly inhibited by indomethacin, which was probably responsible for the delay in the onset of diarrhoea. Indomethacin prevented the enhanced water, K+ and mucus secretion and the reduced Na+ absorption in the colon which were induced by rhein anthrone. The net water secretion could not be reversed to net absorption and the mucus secretion was only slightly depressed by indomethacin. Thus, our findings suggest that other mechanisms, together with the PG-dependent mechanism, are involved in the purgative action of rhein anthrone in rats.     

Drug delivery to the colon using novel one-step, dry-coated tablets (OSDrC)

One-step dry-coated tablets (OSDrC), which are useful as colon-targeting drugs, were prepared using Eudragit L 100-55 (Eud-L) and chitosan (Chit) as an outer layer. The lag time of OSDrC with an outer layer of Eud-L : Chit at a ratio of 3 : 1 in each test medium was greater than the gastric emptying time in the first fluid simulating the stomach and was greater than the small intestine transit time in phosphate buffer (pH 7.4) simulating the small intestine. Drug-release profiles of OSDrC were evaluated under test conditions considering the amount of gastric acid and bile acid, as well as the amount of fluid in the colon. The lag time of OSDrC was greater than the gastric emptying time in test medium simulating the stomach and greater than the small intestine transit time in test medium simulating the small intestine, although it was affected by the amount of gastric acid and bile acid. Drug release from OSDrC was completed within the colonic transit time in the test medium simulating the colon, although it was affected by the amount of fluid in the colon. Therefore the prepared OSDrC were found to permit drug delivery to the colon.     

Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects

BACKGROUND: Serotonin and its type-4 (5-hydroxytryptamine4) receptor play a major role in the physiology of the gastrointestinal tract. The effect of intravenous and/or oral tegaserod, a 5-hydroxytryptamine4 receptor partial agonist, on gastric emptying, small bowel transit and colonic transit has not been studied in detail in humans. AIM: To assess the pharmacodynamic effects of repeated oral and intravenous administration of tegaserod on gastric emptying and small intestine and colonic transit. METHODS: A randomized, placebo-controlled, double-blind, three-way, crossover study of 6 mg oral and 0.6 mg intravenous tegaserod in 12 healthy male subjects was performed. Each treatment arm of the study involved 3 days of twice-daily administration and 1 day of daily administration of the study drugs. RESULTS: In comparison with placebo, oral and intravenous tegaserod significantly increased the gastric emptying rate (P < 0.01), accelerated colonic filling (P < 0.01) and shortened colonic transit at 48 h (P < 0.05). Tegaserod shortened the small intestine transit time by 30% after oral and by 37% after intravenous administration. CONCLUSIONS: In healthy subjects, tegaserod markedly accelerated gastric emptying and small intestinal transit, and induced a small but significant acceleration of colonic transit. Tegaserod can act as a promotile agent throughout the gastrointestinal tract.     

Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging

AIM: The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging. METHODS: Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging. RESULTS: While food intake reduced the mean fluid volumes in the small intestine (105 +/- 72 mL vs. 54 +/- 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 +/- 12 mL vs. 18 +/- 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01). CONCLUSIONS: The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.     

Comparison of in vitro and in vivo performance of a colonic delivery system

The aim of this work is to compare in vitro to in vivo performance of a colonic drug delivery system, made of small pectin-ethylcellulose coated drug beads. The delivery system was evaluated in vitro by conducting drug release studies in different dissolution media to mimic transit times and pH conditions in the stomach, small intestine and colon and in vivo by using gamma-scintigraphic studies in dogs and absorption studies in human volunteers under fed and fasted conditions. In vitro release studies indicated that drug release rate depended on the ratio of the pectin to ethylcellulose in the coat and the thickness of the coat. In vivo release studies obtained by deconvolution of biostudy data did not correlate with in vitro results obtained from most coat formulations. Beads showing ideal release profiles in vitro showed very poor performance in vivo and only those beads showing colonic premature drug release in vitro might be able to deliver the drug to the colon. Scintigraphic studies of a selected formulation showed that the labeled beads had an estimated gastric emptying time of 3 h, an estimated small intestine transit time of 2 h and an estimated colonic transit time of 36 h. Average in vivo lag times of the selected formulation from absorption studies in humans were found to be 6.1 h and 4.8 h under fed and fasted conditions, respectively. The C(max) was also observed at 6.8 h and 5.5 h on average, under fed and fasted conditions, respectively, which might indicate that release of drug from the beads, resulted from degradation of pectin in the coat by enzymatic action in the colon rather than by simple diffusion. Deconvolution of biostudy data showed that drug absorption continued on average for at least 12 h under both fed and fasted conditions.     

Effects of dopamine and bromocriptine on colonic motility in dog.

The effects of intravenous infusions of dopamine (0.1 to 1 mg kg-1h-1) and bromocriptine (10 to 40 micrograms kg-1h-1) on colonic motility were investigated in fasted dogs fitted with permanent strain gauges on the ascending, transverse and descending colon. Infused at rates of 0.5 and 1 mg kg-1h-1 during 1 h, dopamine immediately stimulated the motility of the descending colon; after a delay of 40 to 60 min this effect was balanced by an inhibition of the motility of the ascending and transverse colon. Bromocriptine infused intravenously at doses of 10 to 40 micrograms kg-1h-1 stimulated the motility of the whole colon but these effects were limited to the duration of the infusion (60 min). Both propranolol (0.5 mg kg-1) and tolazoline (2 mg kg-1) failed to block the effects of dopamine and bromocriptine whereas phentolamine (0.1 mg kg-1) and prazosin (0.2 mg kg-1) partially reduced the inhibitory effects of dopamine on the proximal colon. Haloperidol at doses higher than 0.2 mg kg-1 and domperidone blocked the bromocriptine-induced stimulation of colonic motility which was unaffected by previous treatment with alpha- and beta-adrenoceptor blocking agents. These results suggest that in the dog, dopamine and bromocriptine stimulate colonic motility through specific dopamine receptors. However, they suggest that the inhibitory effects of dopamine on the proximal colon which are blocked by dopamine antagonists are also partially due to an effect on alpha 1-adrenoceptors.     

In-vitro and in-vivo studies of pectin/ethylcellulosefilm-coated pellets of 5-fluorouracil for colonic targeting

The aim of the present study was to define in-vitro and in-vivo characteristics of pectin/ethylcellulose-film-coated pellets of 5-fluorouracil (5-FU) for colonic targeting. The pellet cores were coated to different film thicknesses with three different pectin/ethylcellulose formulations using a fluidized bed coater. The gastrointestinal (GI) transit of coated pellets was determined by counting the percentage of coated pellets in the GI lumen by celiotomy at certain times after oral administration. 5FU was administered to rats at a dose of 15 mg kg(-1). The toxicity of 5-FU in the GI tract was evaluated using histological examination. The 1:2 ratio pectin:ethylcellulose-coated pellets with 30% total weight gain (TWG-30%) produced more satisfactory drug-release profiles in the simulated gastric, intestinal and colonic fluids. Most of the coated pellets were eliminated from the stomach in 2 h, moved into the small intestine after 2-4 h, and reached the large intestine after 4 h. After oral administration of coated pellets, 5-FU started appearing in the plasma at 7 h, and reached peak plasma concentration (Cmax) of 3.21+/-2.01 microg mL(-1) at 16 h (Tmax); the Cmax for uncoated pellets was 22.21+/-2.60 microg mL(-1) at Tmax 0.75 h. The TWG-30% formulation showed delayed Tmax, decreased Cmax and prolonged mean residence time compared with uncoated pellets. Marked pathological features in the colon were seen in rats given coated pellets, but no injuries were observed in the upper GI tract. The formulation of TWG-30% could deliver 5-FU to the colon for local action.