Altered pharmacokinetic properties of a lipophilically derivatized low-molecular-weight heparin in rats.
A new generation of lipophilic heparins has been developed that show longer-lasting inhibitory effects on the coagulation system. We have studied the radiopharmacokinetics of a derivatized low-molecular-weight heparin (LMWH) with a residualizing lipophilic tyramine-deoxysorbitol label in comparison with conventional LMWH after intravenous application into Wistar rats. Whole body scintigraphy and analysis of the blood and organ distribution of different tracer preparations revealed that the lipophilically derivatized LMWH substance was predominantly trapped in the liver RES by a scavenger receptor-mediated mechanism. After the saturable uptake mechanism was blocked by maleylated bovine serum albumin, 41.4% of the lipophilic LMWH tracer circulated in blood, as compared with 18.4% of the control and 1% of conventional LMWH. The same results were attained by a competition experiment with an excess of unfractionated heparin. Urinary excretion of the lipophilic tracer among the rats in this competition experiment was considerably lower (13.7%) as compared with conventional LMWH (53.0%). Experiments with lipophilic LMWH tracer bound nonspecifically to rat serum albumin confirmed that the prolonged half-life might in part be due to an increased affinity for albumin. About 59% of the activity of the lipophilic tracer bound to albumin was found in the liver reticuloendothelial system, and only 3.3% were excreted to urine 3 hours after injection. Further studies are necessary to evaluate the accumulation rates and the metabolic fate of lipophilically derivatized heparins in the case of an impeded reticuloendothelial system uptake before attempts are made to therapeutically apply these compounds.
Stehle
G
G
Department of Medicine, Faculty for Clinical Medicine Mannheim, University of Heidelberg, Germany.
Sinn
H
H
Friedrich
E A
EA
Wunder
A
A
Schrenk
H H
HH
Harenberg
J
J
Peschke
P
P
Dempfle
C E
CE
Maier-Borst
W
W
Heene
D L
DL
D000418:Albumins / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D015394:Molecular Structure; D012157:Mononuclear Phagocyte System / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D012710:Serum Albumin, Bovine; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000737:chemistry; D014439:Tyramine / Q000031:analogs & derivatives* / Q000737:chemistry
D000418:Albumins; D006495:Heparin, Low-Molecular-Weight; D007457:Iodine Radioisotopes; D012709:Serum Albumin; C049877:maleylalbumin; C076628:tyramine-deoxysorbitol; D012710:Serum Albumin, Bovine; D013012:Sorbitol; D014439:Tyramine