Dose-dependent stereopharmacokinetics of 5,6-dihydro-4H- 4(isobutylamino)thieno(2,3-B)thiopyran-2-sulfonamide-7,7 -dioxide , a potent carbonic anhydrase inhibitor, in rats

JH Lin, EH Ulm and LE Los

Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.

[5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sul fonamide- 7,7- dioxide] (MK-927), a potent carbonic anhydrase inhibitor capable of reducing intraocular pressure after topical application, is currently under investigation for the treatment of glaucoma. The purpose of this study was to characterize the pharmacokinetics of the enantiomers of MK-927 with particular emphasis on the effect of dose on the elimination kinetics. Because the drug resided primarily in erythrocytes, the kinetic analysis was generally performed based on the drug concentration of whole blood. Following iv administration, the rat cleared the (R)(-)-enantiomer more rapidly than the (S)(+)-isomer. The stereoselective difference in elimination kinetics was dose-dependent; total blood clearance of the (R)(-)-enantiomer was approximately 40 times that of the (S)(+)-isomer at 0.05 mg/kg, and about 7-fold at 5 mg/kg. For both enantiomers, the pharmacokinetic parameters remained unchanged when the dose increased from 0.05 to 0.2 mg/kg, while the total blood clearance and apparent volume of distribution increased substantially as the dose exceeded 2 mg/kg. Nevertheless, the terminal half-life for each enantiomer appeared to be dose-independent. The enantiomers were extensively bound to erythrocytes in a stereoselective manner; at low concentrations, the (S)(+)enantiomer was bound 3-fold more strongly than the (R)(-)-enantiomer in vitro and 6-fold in vivo. Clearly, the magnitude of stereoselectivity in the elimination kinetics of MK-927 enantiomers (40-fold) cannot be explained solely by stereoselective binding. Thus, other factors may also contribute to the overall stereoselectivity in the elimination kinetics of MK-927. The dose-dependent kinetics of the enantiomers was probably due to the saturable binding to carbonic anhydrase.

Volume 19, Issue 1, pp. 233-238, 01/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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