Species-dependent stereopharmacokinetics of MK-927, a potent carbonic anhydrase inhibitor.
MK-927 [5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sul fonamide -7,7 dioxide], a potent carbonic anhydrase inhibitor, contains a chiral center and is a mixture of two forms, R-(-)- and S-(+)-enantiomer. The latter has recently been designated as MK-417. Following iv administration of each enantiomer (0.05 mg/kg), dogs, rabbits, and rats cleared the R-(-)-enantiomer more rapidly than the S-(+)-enantiomer. The elimination clearance of the R-(-)-enantiomer was 2.01 +/- 0.34, 30.0 +/- 2.1, and 53.6 +/- 6.4 ml/hr/kg for dogs, rabbits, and rats, respectively. The corresponding values for the S-(+)-isomer were 0.0380 +/- 0.008, 1.15 +/- 0.20, and 1.29 +/- 0.09 ml/hr/kg. The ratio of the clearance of the R-(-)-enantiomer to that of the S-(+)-isomer was approximately 53 for the dog, 42 for the rat, and 26 for the rabbit, indicating that the degree of stereoselectivity in elimination kinetics of MK-927 enantiomers was species-dependent. Binding of the enantiomers to erythrocytes, presumably carbonic anhydrase, was also stereoselective and species-dependent; the S-(+)-enantiomer was bound more strongly than the R-(-)-isomer in all species. For both enantiomers, binding to carbonic anhydrase was found to be more extensive in dogs than in other species studied. The elimination clearance of the enantiomers in all species was roughly related to their binding affinity, greater Kd1 values being associated with more rapid clearance. However, binding data alone cannot quantitatively explain the degree of the species-dependent stereoselectivity in the elimination kinetics; other factors may also contribute.(ABSTRACT TRUNCATED AT 250 WORDS)
Lin
J H
JH
Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Chen
I W
IW
Lin
T H
TH
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D004912:Erythrocytes / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013237:Stereoisomerism; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics*
D001798:Blood Proteins; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C057921:sezolamide