Evidence for a saturable mechanism of disappearance of standard heparin in rabbits.
This work demonstrates that after bolus intravenous injection standard heparin (SH) disappearance results from the combination of a saturable and a non saturable mechanism. Pharmacokinetics and pharmacodynamics of SH were studied by measuring the disappearance of increasing doses (5 - 500 anti-factor Xa U/kg) of 125I-heparin and of its biological effects. CPM curves allowed to determine the half lives of heparin according to the dose injected. The half lives were clearly dose dependent and reached a plateau over 100 anti-factor Xa U/kg. The complex curve which describes the amount of heparin cleared per time unit after any given dose has been resolved into its two components reflecting a saturable and a non saturable mechanism of disappearance. For the doses less than 100 anti-factor Xa U/kg the saturable mechanism was preeminent and the anti-factor Xa activity disappearance followed an exponential pattern; for the doses less than 100 anti-factor Xa U/kg the contribution of the non saturable mechanism becomes more important and the anti-factor Xa activity disappearance followed a concave-convex pattern. Further experiments showed that the heparin half life shortened as the circulating anti-factor Xa activity decreased; this phenomenon may explain the concave-convex pattern of the curve of the anticoagulant effect observed after injection of large doses of SH.
D000818:Animals; D001822:Body Burden; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000097:blood / Q000378:metabolism*; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D010314:Partial Thromboplastin Time; D011817:Rabbits
D007457:Iodine Radioisotopes; D006493:Heparin