Document Detail


Vesico-hepato-renal cycling of acidic drugs via their reactive acyl glucuronide metabolites? Studies with diflunisal in rats.
MedLine Citation:
PMID:  8886486     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1. Deconjugation-reconjugation cycling of acidic drugs is known to occur in vivo via the hydrolysis of their reactive acyl glucuronide metabolites during their circulation in the blood (systemic cycling) or during their passage through the gut after biliary excretion (enterohepatic cycling). Whether such cycling occurs after renal excretion via hydrolysis in the urinary bladder followed by absorption of liberated drug (vesico-hepato-renal cycling) was investigated in rats using diflunisal (DF) and its acyl glucuronide (DFAG) as model compounds. 2. After administration of DF (1 mg/0.5 mL buffer, pH 7) into the bladder of anaesthetized bile-exteriorized rats, DF appeared rapidly in plasma, achieving peak concentrations of 7 micrograms/mL at 1 h. At 4 h, 30% of the dose was recovered as metabolites, mainly DFAG and DF phenolic glucuronide (DFPG) in bile, while 30% was recovered as unchanged DF from the bladder. 3. By contrast, after intravesical administration of an equimolar amount of DFAG at pH 7 or 5, DFAG itself was not detectable in plasma. Plasma concentrations of DF were barely detectable, with only approximately 1% of the administered dose recovered as metabolites in bile. 4. The data thus show that, although DF itself undergoes facile absorption from the urinary bladder of healthy rats, vesico-hepato-renal cycling of DF via DFAG appears to be of only minor quantitative importance.
Authors:
R G Dickinson; A R King
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical and experimental pharmacology & physiology     Volume:  23     ISSN:  0305-1870     ISO Abbreviation:  Clin. Exp. Pharmacol. Physiol.     Publication Date:  1996 Aug 
Date Detail:
Created Date:  1997-02-06     Completed Date:  1997-02-06     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0425076     Medline TA:  Clin Exp Pharmacol Physiol     Country:  AUSTRALIA    
Other Details:
Languages:  eng     Pagination:  665-8     Citation Subset:  IM    
Affiliation:
Department of Medicine, University of Queensland, Royal Brisbane Hospital, Australia.
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MeSH Terms
Descriptor/Qualifier:
Administration, Intravesical
Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage,  blood,  metabolism*,  urine
Bile / chemistry
Carboxylic Acids / metabolism
Diflunisal / administration & dosage,  blood,  metabolism*,  urine
Glucuronates / blood,  metabolism*,  pharmacokinetics
Glucuronidase / metabolism*
Male
Metabolic Detoxication, Drug
Rats
Rats, Sprague-Dawley
Urinary Bladder / metabolism*
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Carboxylic Acids; 0/Glucuronates; 22494-42-4/Diflunisal; EC 3.2.1.31/Glucuronidase

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