Pharmacokinetics and pharmacodynamics of a low molecular weight heparin (enoxaparin) after subcutaneous injection, comparison with unfractionated heparin--a three way cross over study in human volunteers.
We determined, in volunteers, the plasma levels of heparin above and below the critical chainlength necessary for thrombin inhibition (ACLM and BCLM), from 1 to 24 h after subcutaneous injection of 5000 IU unfractionated heparin (UFH), 40 mg enoxaparin and 1 mg/kg body weight of enoxaparin (LMWH) (n = 12 for each dose). The levels were calculated from the antithrombin- and anti-Xa activities using the specific activities of the materials injected. We also determined the course of thrombin- and of factor Xa generation after triggering the extrinsic system in the same samples. From the thrombin generation curves, we calculated the course of prothrombinase activity. When the ACLM and BCLM plasma-levels are plotted against the inhibition of thrombin- and factor Xa generation, it appears that: a) There is a unique dose response relationship between ACLM level and the inhibition of thrombin generation, independent of whether the ACLM is derived from UFH or LMWH. This relationship is not significantly altered by the BCLM appearing after LMWH injection. b) There is a similar unique relationship between ACLM level and the inhibition of factor Xa generation, again independent of BCLM. c) Inhibition of prothrombin activation hardly contributes to the overall effect on thrombin formation and is again independent of the source of ACLM. d) ACLM levels were significantly higher after injection of LMWH than after UFH injection, even though the amounts of ACLM injected with the highest dose of LMWH were smaller than those administered in the UFH injection. We conclude that the only functional difference between LMWH and UFH is the much higher bioavailability of the former.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Biochemistry, University of Limburg, Maastricht, The Netherlands.
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Bendetowicz
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Béguin
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Caplain
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Hemker
D000328:Adult; D000990:Antithrombin III / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004789:Enzyme Activation; D015951:Factor Xa / Q000032:analysis; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D016037:Single-Blind Method; D013917:Thrombin / Q000032:analysis / Q000037:antagonists & inhibitors; D013925:Thromboplastin / Q000032:analysis
D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D000990:Antithrombin III; D006493:Heparin; D013925:Thromboplastin; D013917:Thrombin; D015951:Factor Xa