Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans.
Low-molecular-weight heparins (LMWHs) comprise a group in the class of antithrombotic medications, a class headed by unfractionated heparin (UFH). The LMWHs, with mean molecular weights of 4.0-6.0 kD, differ in their individual manufacturing processes, the distribution of their fragment molecular weights, their in vitro potency (anti-Xa, antithrombin and anticoagulant activities) and, consequently, in their biodynamic patterns, recommended dose regimen, and efficacy/safety ratio. Their drug disposition profiles have been evaluated using two significant markers of their pharmacodynamic activity, namely anti-Xa and anti-IIa activities. Since they are mainly administered subcutaneously, then compared to UFH, they are almost completely absorbed (F > or = 90%) and, in contrast to UFH, those for which data are available in the literature exhibit linear pharmacokinetics with proportionality between anti-Xa (and anti-IIa in some cases) plasma concentration and dose, and stationary distribution volume and clearance processes when the dosage is increased. Their distribution volume is close to the blood volume, they are partially metabolized by desulphatation and depolymerization, but urinary excretion of anti-Xa activity for enoxaparin, dalteparin and nadroparin, all given at doses for prevention of venous thrombosis, is between 5 and 10% of the injected dose. However, these LMWHs differ in the extent of their non-renal clearance, resulting in different apparent elimination half-life values and relative apparent bioavailability. When considering certain at-risk situations, using doses for preventing thromboembolism, the LMWHs do not significantly cross the placenta of pregnant women and their excretion profiles are only slightly altered in severe (endogenous creatinine clearance less than 15 ml/min) renal disease patients when given at doses recommended for prevention of venous thromboembolism. Because of the differences among LMWHs, the clinical profile of a given LMWH cannot be extrapolated to another one or generalized to the whole LMWH family.
Frydman
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Rhône-Poulenc Rorer SA, Recherche et Développement, Antony, France.
D000368:Aged; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D007408:Intestinal Absorption; D011247:Pregnancy; D014018:Tissue Distribution
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight