Pharmacokinetics of tinzaparin (Logiparin®) - a low molecular weight heparin-after single and repeated intravenous administration in rats

Abstract

After a single and repeated i.v. injections of 1 mg/kg 3H-radiolabelled tinzaparin once daily to rats for 7, 14, and 21 days, drug-related radioactivity in plasma, tissues, urine and faeces was measured by use of liquid scintillation counting. The decay in plasma could be described by a three-compartment model with half-lives of the two distributive phases and the terminal elimination phase of 15 min, 90 min, and 37 hrs, respectively. The peak plasma concentration did not change during repeated dosing, as opposed to the trough concentration which increased 3 fold. The decay in tissues was significantly different from that in plasma, and showed less fluctuations. Drug-related radioactivity accumulated gradually with repeated dosing, reaching accumulation ratios between 5 and 9, when based on trough concentrations. Slow elimination was observed from tissues, and significant amounts were still present 14 days after discontinuation of the repeated dosing. In the liver, the concentrations were almost constant during a dosing interval. After a single injection, 86% and 4% of the administered radioactive dose were excreted in urine and faeces over 7 days, respectively, the majority being recovered during the first 24 hrs, demonstrating that the major route of elimination was by renal excretion. The molecular mass distribution of radioactivity in urine was similar but not identical to the injected test substance. It was shifted slightly towards lower molecular mass and had no anti-factor Xa activity, suggesting that the heparin was either inactivated, presumably by desulphation, or that the antithrombin binding portion of the drug was cleared through a different route.