Different pharmacokinetics, antithrombotic activity and bleeding effects of heparin and two new fragments administered in rat by subcutaneous route.
Native heparin (CAS 9005-49-6) and its two new fragments, low molecular weight heparin (LMW-H, 5 kDa) and oligo-heparin (oligo-H, 2 kDa) obtained by radical degradation were characterized as to their physicochemical properties. Heparin fragments differ from unfractionated heparin only in molecular weight. The pharmacokinetics and some pharmacological effects, bleeding and antithrombotic activity, of the three different molecular weight heparins were investigated. The plasma concentrations were determined by an amidolytic method which measures inhibiting effect on factor Xa. The blood levels of each substance were derived from their in vitro calibration curves. The examination of the pharmacokinetics parameters allowed to evaluate the differences in the bioavailability, absorption rate and elimination mechanisms between the three different heparins. The bioavailability, the absorption rate and the distribution of the molecules of heparins in biological compartments depend on the molecular weight. LMW-H and oligo-H exhibit greater antithrombotic activity than unfractionated heparin when administered subcutaneously. The pharmacokinetic behaviour of oligo-H considerably differs from that of unfractionated heparin and LMW-H. This new drug is able to bind cells and plasma proteins differently from heparin and LMW-H. The capacity of oligo-H to bind smooth muscle cells and to interact with myosin is discussed in relation to the bleeding effect.
Bergonzini
G L
GL
Opocrin S.p.A., Research Laboratories, Corlo-Modena, Italy.
Bianchini
P
P
Mascellani
G
G
Osima
B
B
Parma
B
B
Volpi
N
N
D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004587:Electrophoresis, Agar Gel; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced*; D006493:Heparin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019763:Heparin Lyase; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011133:Polysaccharide-Lyases / Q000378:metabolism; D051381:Rats; D014574:Uronic Acids / Q000494:pharmacology
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D010446:Peptide Fragments; D014574:Uronic Acids; D006493:Heparin; D011133:Polysaccharide-Lyases; D019763:Heparin Lyase