Rearrangement of diflunisal acyl glucuronide into its beta-glucuronidase-resistant isomers facilitates transport through the small intestine to the colon of the rat.
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 microg 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 < or = 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 degrees C. Upper small intestine, lower small intestine, caecum and colon released 2400, 3200, 9200 and 22800 microg DF/hr/g tissue plus contents respectively from DAG substrate, and 18, 10, 140 and 120 microg 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.
Dickinson
R G
RG
Centre for Studies in Drug Disposition, Department of Medicine, The University of Queensland at Royal Brisbane Hospital, Australia. r.dickinson@medicine.uq.edu.au
King
A R
AR
D000818:Animals; D021461:Animals, Outbred Strains; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001692:Biological Transport; D003106:Colon / Q000378:metabolism*; D004061:Diflunisal / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005966:Glucuronidase / Q000737:chemistry / Q000378:metabolism*; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C041944:diflunisal glucuronide ester; D004061:Diflunisal; D005966:Glucuronidase