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 f ragment molecular weights, their in vitro potency (anti-Xa, antithromb in and anticoagulant activities) and, consequently, in their biodynami c patterns, recommended dose regimen, and efficacy/safety ratio. Their drug disposition profiles have been evaluated using two significant m arkers of their pharmacodynamic activity, namely anti-Xa and anti-IIa activities. Since they are mainly administered subcutaneously, then co mpared to UFH, they are almost completely absorbed (F greater than or equal to 90%) and, in contrast to UFH, those for which data are availa ble in the literature exhibit linear pharmacokinetics with proportiona lity 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 th e blood volume, they are partially metabolized by desulphatation and d epolymerization, but urinary excretion of anti;Xa activity for enoxapa rin, dalteparin and nadroparin, all given at doses for prevention of v enous thrombosis, is between 5 and 10% of the injected dose. However, these LMWHs differ in the extent of their non-renal clearance, resulti ng in different apparent elimination half-life values and relative app arent bioavailability. When considering certain at-risk situations, us ing doses for preventing thromboembolism, the LMWHs do not significant ly cross the placenta of pregnant women and their excretion profiles a re only slightly altered in severe (endogenous creatinine clearance le ss than 15 ml/min) renal disease patients when given at doses recommen ded for prevention of venous thromboembolism. Because of the differenc es among LMWHs, the clinical profile of a given LMWH cannot be extrapo lated to another one or generalized to the whole LMWH family.