Synthetic analogues of the antithrombin III-binding pentasaccharide sequence of heparin. Prediction of in vivo residence times.
The synthetic pentasaccharide Org 31540/SR 90107A represents the antithrombin III (ATIII) binding region of heparin and accelerates the ATIII-mediated inhibition of coagulation factor Xa. This compound and 15 structural analogues with ATIII binding constants (Kd) ranging from 2.7 to 2600 nmol/L were compared for their plasma elimination in rats as measured from their factor Xa inhibiting activity. After administration of a low dose (100 nmol/kg body wt IV), each pentasaccharide showed a characteristic plasma half-life varying from a minimum of 0.3 hour for pentasaccharides with low affinity for ATIII to 10.9 hours for pentasaccharides with high affinity for the protein. The latter value was close to the half-life measured for radioiodinated rat ATIII (11.8 hours). We hypothesized that the elimination half-life of pentasaccharides is markedly extended by ATIII binding, of which the extent is governed by the Kd of the complex. The following observations support this hypothesis. The low-dose, low-affinity pentasaccharides were almost fully recovered in the urine without having lost anti-factor Xa activity, whereas compounds with high ATIII binding affinity were only partly recovered in the urine. With a high dose (500 nmol/kg body wt), a rapid plasma clearance of pentasaccharide was observed until a concentration similar to that of endogenous ATIII was reached, in accordance with their expected 1:1 stoichiometric interaction. The elimination of half-life was similar to that of the low dose. The relation between Kd values and plasma half-lives could be explained by assuming rapid clearance of free and coclearance of ATIII-bound pentasaccharide with the protein.(ABSTRACT TRUNCATED AT 250 WORDS)
van Amsterdam
R G
RG
Scientific Development Group, N.V. Organon, Oss, The Netherlands.
Vogel
G M
GM
Visser
A
A
Kop
W J
WJ
Buiting
M T
MT
Meuleman
D G
DG
D000818:Animals; D000990:Antithrombin III / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002240:Carbohydrate Sequence; D006207:Half-Life; D006493:Heparin / Q000097:blood / Q000737:chemistry*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009844:Oligosaccharides / Q000097:blood / Q000138:chemical synthesis / Q000652:urine; D051381:Rats; D017208:Rats, Wistar
D009844:Oligosaccharides; D000990:Antithrombin III; D006493:Heparin