Document Detail

Intestinal absorption of captopril and two thioester analogs in rats and dogs.
MedLine Citation:
PMID:  9008267     Owner:  NLM     Status:  MEDLINE    
The objectives of this study were (i) to determine whether the reduced absorption of captopril from the colon of humans also occurs in rats and (ii), after confirmation of the relevance of a new rat model, to evaluate the intestinal absorption of captopril and several of its analogs. A model was developed and validated in which specific sites within the GI tract of rats were surgically implanted with a cannula such that animals could be dosed while conscious and unrestrained. The absorption of captopril after administration into the lower GI tract of rats was significantly reduced relative to the upper GI tract, which was consistent with results reported previously in humans. In rats, the absorption of the S-benzoyl thioester prodrug of captopril (SQ-25868) from the lower GI tract was substantially greater than that of captopril. However, the absorption of the S-benzoyl thioester prodrug of 4-phenyl thio-captopril (SQ-26991) from the lower GI tract was only marginally better than that of captopril. In additional studies in dogs, a 12h controlled-release formulation of SQ-25868 provided sustained blood levels of captopril while maintaining acceptable bioavailability (> 80%). Two approaches were tried, without success, to stabilize captopril in vivo: (i) complexation with zinc (SQ-26284) and (ii) use of ascorbic-acid-buffered (pH 3.5) vehicle. The zinc complex might have failed because it has very low solubility, whereas the pH-3.5-buffered vehicle was quickly neutralized within the colonic lumen in rats, and did not stabilize captopril against oxidation. Rapid neutralization might explain why the colonic bioavailability of captopril was not substantially increased when this pH-3.5-buffered vehicle was tried in humans.
R A Morrison; K J Kripalani; A M Marino; A V Dean; B H Migdalof; S H Weinstein; N B Jain; M S Bathala; S M Singhvi
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Biopharmaceutics & drug disposition     Volume:  18     ISSN:  0142-2782     ISO Abbreviation:  Biopharm Drug Dispos     Publication Date:  1997 Jan 
Date Detail:
Created Date:  1997-03-25     Completed Date:  1997-03-25     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7911226     Medline TA:  Biopharm Drug Dispos     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  25-39     Citation Subset:  IM    
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08540, USA.
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MeSH Terms
Angiotensin-Converting Enzyme Inhibitors / pharmacokinetics*
Captopril / analogs & derivatives*,  pharmacokinetics*
Chromatography, Thin Layer
Intestinal Absorption
Prodrugs / pharmacokinetics*
Rats, Sprague-Dawley
Species Specificity
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Prodrugs; 62571-86-2/Captopril; 75714-71-5/S-benzoyl captopril; 81872-10-8/zofenopril

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