Effects of N-deacetylation and N-desulfation of heparin on its anticoagulant activity and in vivo disposition.
This investigation compares the anticoagulant activities and in vivo disposition characteristics of N-deacetylated heparin and N-desulfated heparin with those of standard heparin in an animal model. The N-deacetylated heparin retained 23% of the anticoagulant activity, 34% of the anti-Xa activity and 23% of the anti-IIa activity of standard heparin, whereas the N-desulfated heparin retained only 1.5% of the anticoagulant activity, 0.095% of the anti-Xa activity and 0.92% of the anti-IIa activity of the original heparin. After i.v. injections of 5 mg/kg of the modified heparins, both N-deacetylated and N-deacetylated heparin concentrations showed monoexponential declines with time. The elimination half-lives were similar, 11.7 +/- 3.8 and 13.5 +/- 5.2 min, respectively (N.S.). There were, however, significant differences in both total clearance (Cl) and apparent volume of distribution (Vd) for these heparins, both parameters being significantly larger for the N-deacetylated heparin (P = .0007). The Cl values were 4.15 +/- 1.11 and 0.58 +/- 0.26 ml/min/kg and the Vd values were 72.1 +/- 38.7 and 9.9 +/- 2.4 ml/kg for the N-deacetylated and N-desulfated heparins, respectively. We have reported previously that after a similar dose of standard heparin the elimination half-life was 69.0 +/- 13.1 min, Cl was 0.64 +/- 0.16 ml/min/kg and Vd was 62.6 +/- 16.7 ml/kg. These studies have thus demonstrated that selective N-deacetylation and N-desulfation of the glucosamine residues of heparin affect markedly both its anticoagulant activity and in vivo disposition characteristics. Although important for full anticoagulant activity of heparin, the N-acetyl groups are apparently not essential.(ABSTRACT TRUNCATED AT 250 WORDS)
Bjornsson
T D
TD
Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Schneider
D E
DE
Hecht
A R
AR
D000107:Acetylation; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D015951:Factor Xa; D006493:Heparin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010314:Partial Thromboplastin Time; D011516:Prothrombin / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D015842:Serine Proteinase Inhibitors; D013329:Structure-Activity Relationship; D013431:Sulfates
D015842:Serine Proteinase Inhibitors; D013431:Sulfates; D011516:Prothrombin; C025337:Factor IIa; D006493:Heparin; D015951:Factor Xa