Rearrangement of diflunisal acyl glucuronide into its beta-glucuronidase-resistant isomers facilitates transport through the small intestine to the colon of the rat

Dickinson, Ronald G. and King, Andrew R. (2001) Rearrangement of diflunisal acyl glucuronide into its beta-glucuronidase-resistant isomers facilitates transport through the small intestine to the colon of the rat. Life Sciences, 70 1: 25-36. doi:10.1016/S0024-3205(01)01371-6


Author Dickinson, Ronald G.
King, Andrew R.
Title Rearrangement of diflunisal acyl glucuronide into its beta-glucuronidase-resistant isomers facilitates transport through the small intestine to the colon of the rat
Formatted title
Rearrangement of diflunisal acyl glucuronide into its β-glucuronidase-resistant isomers facilitates transport through the small intestine to the colon of the rat
Journal name Life Sciences   Check publisher's open access policy
ISSN 0024-3205
Publication date 2001
Sub-type Article (original research)
DOI 10.1016/S0024-3205(01)01371-6
Volume 70
Issue 1
Start page 25
End page 36
Total pages 12
Editor Rubin Bressler
S. Z. Langer
Place of publication USA
Publisher Elsevier Science Inc
Collection year 2001
Language eng
Subject C1
320504 Toxicology (incl. Clinical Toxicology)
730199 Clinical health not specific to particular organs, diseases and conditions
Abstract Many non-steroidal anti-inflammatory drugs (NSAIDs) which form acyl glucuronide conjugates as major metabolites have shown an antiproliferative effect on colorectal tumors. This study assesses the extent to which rearrangement of an acyl glucuronide metabolite of a model NSAID into beta -glucuronidase-resistant isomers facilitates its passage through the small intestine to reach the colon. Rats were dosed orally with diflunisal (DF), its acyl glucuronide (DAG) and a mixture of rearrangement isomers (iso-DAG) at 10 mg DF equivalents/kg. The parent drug DF appeared in plasma after all doses, with maximum concentrations of 20.5 +/- 2.5, 28.8 +/- 8.3 and 11.0 +/- 1.6 mug DF/ml respectively, obtained at 3.8 +/- 0.3, 3.6 +/- 1.8 and 7.5 +/- 0.9 hr after the DF, DAG and iso-DAG doses respectively. At 48 hr, 16.2 +/- 3.3, 19.8 +/- 0.8 and 42.9 +/- 10.1% of the doses respectively were recovered in feces, with less than or equal to 1% remaining in the intestine. About half of each dose was recovered as DF and metabolites in 48 hr urine: for DF and DAG doses, the majority was in the first 24 hr urine. whereas for iso-DAG doses, recoveries in the first and second 24 hr periods were similar. The results show that hydrolysis of both DAG and iso-DAG, and absorption of liberated DF, occur during passage through the gut, but that these processes occur more slowly and to a lesser degree for iso-DAG. The intrinsic hydrolytic capacities of various intestinal segments (including contents) towards DAG and iso-DAG were obtained by incubating homogenates under saturating concentrations of DAG/iso-DAG at 37 degreesC. Upper small intestine, lower small intestine, caecum and colon released 2400, 3200, 9200 and 22800 mug DF/hr/g tissue plus contents respectively from DAG substrate, and 18, 10, 140 and 120 mug DF/hr/g tissue plus contents respectively from iso-DAG substrate. The much greater resistance of iso-DAG to hydrolysis appears attributable to its resistance to beta -glucuronidases. The data suggest that in rats dosed with DF, DAG excreted in bile would be substantially hydrolysed in the small intestine and liberated DF reabsorbed, but that portion which rearranges to iso-DAG would likely reach the colon. (C) 2001 Elsevier Science Inc. All rights reserved.
Keyword Medicine, Research & Experimental
Pharmacology & Pharmacy
Diflunisal
Acyl Glucuronide
Rearrangement
Beta-glucuronidase
Colon Cancer
Nonsteroidal Antiinflammatory Drugs
Covalent Binding
Renal-failure
Serum-albumin
Acidic Drugs
Plasma
Liver
Disposition
Reactivity
Excretion
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Tue, 14 Aug 2007, 15:42:29 EST