Interspecies differences in stereoselective protein binding and clearance of MK-571.
(+)-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.
Tocco
D J
DJ
Merck, Sharpe & Dohme Research Laboratory, Division of Merck Company, West Point, PA 19486.
deLuna
F A
FA
Duncan
A E
AE
Hsieh
J H
JH
Lin
J H
JH
D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000032:analysis; D006207:Half-Life; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D011422:Propionates / Q000493:pharmacokinetics*; D011485:Protein Binding; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013237:Stereoisomerism
D001798:Blood Proteins; D011422:Propionates; D011804:Quinolines; C059141:verlukast