STEREOSELECTIVE ASPECTS IN THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ACENOCOUMAROL AND ITS AMINO AND ACETAMIDO DERIVATIVES IN THE RAT

  • 1 January 1985
    • journal article
    • research article
    • Vol. 13  (5) , 593-597
Abstract
The stereoselectivity of the pharmacokinetics and of the pharmacodynamics of the oral anticoagulant acenocoumarol (AC) and of two of its potential metabolites, the amino (AM) and the acetamido (AA) derivatives, were investigated in the rat. The pharmacokinetics and pharmacodynamics were investigated following the acute subcutaneous (1 mg/kg) administration of the pure enantiomers. For AC and AA, the S(-)-enantiomer was preferentially eliminated, whereas for AM the R(+)-enantiomer showed the shortest half-life. The differences in elimination between the AC enantiomers were entirely due to differences in total clearance, 183 .+-. 14 and 714 .+-. 148 ml .cntdot. h-1 .cntdot. kg-1 (.+-. SD) for R(+)- and S(-)-AC. Also the differences in elimination between the AM enantiomers were mainly due to differences in body clearance, 50 .+-. 13 and 18 .+-. 4 ml .cntdot. h-1 .cntdot. kg-1 for R(+)- and S(-)-AM. For S(-)-AA the higher total clearance as well as the smaller volume of distribution accounted for its 2-fold higher rate of elimination. Acetylation of AM, i.e., the conversion to AA, which accounted for about 50% of its total clearance was stereoselective for R(+)-AM. The renal clearance of AA which accounted for 50-60% of the AA clearance was not selective for one of the AA enantiomers. Stereoselectivity in plasma protein binding was observed, the differences, however, were small. Thus, stereoselectivity in plasma protein binding did not account for the observed differences in the pharmacokinetics. The differences in anticlotting activity between the enantiomers of AC and AM were determined mainly by their pharmacokinetics. Close observation, however, showed that the S-configuration intrinsically was the most active one.