Document Detail

Interspecies differences in stereoselective protein binding and clearance of MK-571.
MedLine Citation:
PMID:  1976057     Owner:  NLM     Status:  MEDLINE    
(+)-3-(((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-(dimethylamino)- 3-oxopropyl)thio)methyl)thio)propanoic acid (MK-571), is a potent and specific antagonist of leukotriene D4 action in vitro and in vivo. The compound, which is being developed for the treatment of asthma, contains a chiral center at the methine carbon of the dithio side chain and exists in two forms. The binding of MK-571 enantiomers to plasma protein was extensive (greater than 99.5%), stereoselective, and species dependent. The R-(-)-enantiomer was bound to rat plasma to a greater extent than the S-(+)-enantiomer, while in dog and monkey plasma the reverse was the case. The elimination clearance of the enantiomers was inversely related to the stereoselective plasma protein binding, that with the greater unbound fraction being cleared more rapidly. Thus, the pharmacologically more active S-(+)-enantiomer was cleared 3.7 times more rapidly than its antipode in rats following iv administration of the racemate (10 mg/kg), whereas in dogs and monkeys the R-(-)-enantiomer was cleared more rapidly. Kinetic analysis of the data revealed that the intrinsic clearances of the unbound enantiomers were similar within species, suggesting that stereoselectivity in elimination is not attributable to differences in metabolism and biliary excretion. Bioavailabilities of the S-(+)- and R-(-)-enantiomers in the rat were similar (75% and 71%, respectively) suggesting that MK-571 was not stereoselectively absorbed in that species.
D J Tocco; F A deLuna; A E Duncan; J H Hsieh; J H Lin
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  18     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:    1990 Jul-Aug
Date Detail:
Created Date:  1990-10-19     Completed Date:  1990-10-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  388-92     Citation Subset:  IM    
Merck, Sharpe & Dohme Research Laboratory, Division of Merck Company, West Point, PA 19486.
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MeSH Terms
Biological Availability
Blood Proteins / metabolism
Chromatography, High Pressure Liquid
Feces / analysis
Macaca mulatta
Propionates / pharmacokinetics*
Protein Binding
Quinolines / pharmacokinetics*
Rats, Inbred Strains
Species Specificity
Reg. No./Substance:
0/Blood Proteins; 0/Propionates; 0/Quinolines; 115104-28-4/verlukast

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