Document Detail


Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs--II. Racemization and hydrolysis of (R)- and (S)-ibuprofen-CoA thioesters.
MedLine Citation:
PMID:  1741768     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The inversion of 2-arylpropionic acids (2-APAs) has become the subject of much attention. It is a unique reaction specific to this group of drugs. Inversion proceeds via stereoselective activation of the R-enantiomer to its CoA thioester whereby it is then racemized and hydrolysed to release free drug. The racemization and hydrolysis processes have been examined in this study using chemically synthesized CoA thioesters of the ibuprofen enantiomers and in vitro models employing rat liver homogenate and the mitochondrial and microsomal fractions as the source of the 'racemase' enzymes. Rat liver homogenate mediated the racemization and hydrolysis of both (R)- and (S)-ibuprofen-CoA thioesters. The rat liver mitochondrial fraction similarly mediated racemization and hydrolysis of both CoA thioesters. There was less racemase activity in the rat liver microsomal fraction and the data indicated that this fraction may contain two hydrolases which act separately on the (R)- and (S)-ibuprofen-CoA thioesters. The data are further evidence that the stereoselectivity of the CoA synthetase controls the overall stereoselectivity of inversion.
Authors:
R D Knihinicki; R O Day; K M Williams
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  42     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1991 Oct 
Date Detail:
Created Date:  1992-01-03     Completed Date:  1992-01-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1905-11     Citation Subset:  IM    
Affiliation:
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, N.S.W., Australia.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemistry,  metabolism*
Esters / chemical synthesis,  chemistry
Hydrolases
Ibuprofen / chemistry,  metabolism*
Liver / metabolism*
Male
Rats
Rats, Inbred Strains
Stereoisomerism
Subcellular Fractions / metabolism
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Esters; 15687-27-1/Ibuprofen; EC 3.-/Hydrolases

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