Enterohepatic circulation of indomethacin and its role in intestinal irritation

Duggan, D E; Hooke, K F; Noll, R.M.; Kwan, K.C.

doi:10.1016/0006-2952(75)90450-5

Cited by 163 publications

(61 citation statements)

References 4 publications

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“…Dependency, both on dose and duration of exposure, is a characteristic of other non-steroidal anti-inflammatory agents . For indomethacin, it is known that intestinal lesions in rats depend on the excretion of the active drug in the bile (Brodie et al, 1970;Duggan et al, 1975). As has been shown by Tocco et al (1975), diflunisal was excreted to some extent in the bile in the rat.…”

Section: Discussionmentioning

confidence: 86%

Pharmacology and toxicology of diflunisal.

Stone¹,

Arman²,

Vj³

et al. 1977

Brit J Clinical Pharma

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1 Diflunisal, a new salicylate, possesses anti-inflammatory, analgesic and antipyretic activity. It was found to be about 7.5-13 times more active than aspirin as an analgesic (Randall-Selitto assay in rats) and as an anti-inflammatory agent (carrageenin foot oedema and adjuvant arthritis in rats). 2 Diflunisal was 1.4 times as active as aspirin as an antipyretic in the rat and about three times as potent in reducing lameness induced by injecting urate crystals into the knee joint of dogs. 3 Diflunisal inhibited adenosine diphosphate, adrenaline and thrombin-induced aggregation of human platelets in vitro. The concentrations required were 18-35 times higher than those needed with aspirin.4 After single doses, both diflunisal and aspirin induced gastric haemorrhages in starved rats. This was evident only after relatively large doses of diflunisal, whereas aspirin induced gastric changes after pharmacologically active amounts. 5 Diflunisal, but not aspirin, after single doses, produced perforations of the small intestine in the rat. The dose levels required were considerably above those that would demonstrate anti-inflammatory and analgesic activity. 6 In oral subacute toxicity studies in rats and dogs of 14 weeks' duration, diflunisal and aspirin produced similar gastric and renal toxicity. Both produced focal oedema, haemorrhage and small ulcers in one or both species. Renal changes were limited to a slight degree of oedema of the papilla in the rat and dog. Diflunisal, but not aspirin, produced intestinal lesions of the small bowel in the rat but not the dog. The changes with either drug were largely limited to the higher levels used (50-200 mg/kg/d).

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Section: Discussionmentioning

confidence: 86%

Pharmacology and toxicology of diflunisal.

Stone¹,

Arman²,

Vj³

et al. 1977

Brit J Clinical Pharma

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“…Animal experiments have shown that certain NSAIDs may cause ileal and jejunal lesions, dependent on the degree of enterohepatic circulation of the drug in a given species (Duggan et al, 1975). Literature data on the degree of biliary excretion and recirculation of NSAIDs in man, however, are scarce (Brune & Lanz, 1985;Verbeeck, 1988).…”

Section: Introductionmentioning

confidence: 99%

Biliary elimination of non‐steroidal anti‐inflammatory drugs in patients.

Schneider

Nuernberg

Dietzel

et al. 1990

Brit J Clinical Pharma

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In view of evidence in animals that enterohepatic recirculation of non-steroidal antiinflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin.

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“…hepatic circulation of NSAIDs and their metabolites (2,9,29). The gastric and duodenal or ileal damage caused by NSAID toxicity are explained by different factors such as acid and pepsin or intestinal bacteria, respectively (3,26).…”

mentioning

confidence: 99%

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

Uejima

Kinouchi

Kataoka

et al. 1996

Microbiology and Immunology

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The role of intestinal bacteria in induction and repression of ulcer formation in the ileum of rats treated with one of the nonsteroidal antiinflammatory drugs (NSAIDs), 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT), was examined in this study. BFMeT was administered by intragastric gavage once at doses of 500-1,500 mg/kg of body weight to Wistar rats treated with and without antibiotics (bacitracin, neomycin, streptomycin), germ-free rats and gnotobiotic rats, and 72 hr later their gastrointestinal tracts were examined for ulcer formation. A single oral administration of BFMeT induced ileal ulcers in specific pathogen-free rats. However, the rats given antibiotics to reduce the intestinal bacteria had no ulcers. BFMeT-treated germ-free rats and gnotobiotic rats mono-associated with Bifidobacterium adolescentis or Lactobacillus acidophilus also had no intestinal ulcers. However, the drug induced ileal ulcers in gnotobiotic rats mono-associated with Eubacterium limosum or Escherichia coli. An overnight culture of B. adolescentis or L. acidophilus or yogurt containing Bifidobacterium breve and Streptococcus thermophilus, when given as drinking water, inhibited ulcer formation in the ileum of rats treated with BFMeT. Gram staining of the ileal contents of normal rats revealed that 97.4% of the stained microorganisms were Gram-positive rods and only 1.2 % were Gram-negative rods. In the group of rats with ulcers induced by BFMeT, the Gram-positive rods decreased by 56.4% and the Gram-negative rods including Escherichia coli, Klebsiella, Proteus and Bacteroides increased by 37.3%. However, in the group of rats administered the Bifidobacterium culture, the Lactobacillus culture or yogurt, the percentages of the Gram-negative rods were decreased. Although Lactobacillus was a major bacterium in the ileum of normal rats, the Gram-negative facultatively anaerobic rods E. coli, Klebsiella and Proteus were increased in the ulcerated ileum of rats treated with BFMeT, suggesting that these bacteria are associated with ulcer formation in rats treated with NSAIDs, and that Lactobacillus and Bifidobacterium inhibit it by repressing the growth of ulcer-inducing bacteria.

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Enterohepatic circulation of indomethacin and its role in intestinal irritation

Cited by 163 publications

References 4 publications

Pharmacology and toxicology of diflunisal.

Pharmacology and toxicology of diflunisal.

Biliary elimination of non‐steroidal anti‐inflammatory drugs in patients.

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

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