The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg.

The pharmacokinetics of enoxaparine, a low molecular weight heparin, was randomly studied in 12 healthy male volunteers. Doses of 20, 40, 60, and 80 mg were injected subcutaneously in randomized cross-over fashion. Anti-IIa and anti-Xa activities (using amidolytic methods), and calcium thrombin time, were measured over 36 hours. The maximum Amax of the anti-IIa and anti-Xa activities appeared 3 to 4 hours after administration. The terminal half-lives of anti-IIa and anti-Xa activities were approximately 2 and 4 hours, respectively, with no significant variation between the different doses. For the anti-Xa activity, there was a highly significant positive correlation between the dose injected and individual values of Amax (r = +0.915; P less than .001) and AUC (r = +0.913; P less than .001). Enoxaparine displays a relatively small apparent volume of distribution (about 7.0 L) and its total body clearance is about 1.25 L/hr. The mean residence time ranges from 4.6 to 7.6 hours. Thus, the pharmacokinetic profile of enoxaparine is characterized by a linear relationship between dose and absorption, a relatively low clearance and long elimination half-life, and a high anti-Xa/anti-IIa ratio.

Effect of probenecid on isofezolac kinetics.

The interaction between isofezolac and probenecid has been studied with the aid of a specific HPLC assay for isofezolac in plasma and urine. 8 healthy adult volunteers received a single 40 mg oral dose of isofezolac before and after 3 days of loading with 0.5 probenecid t.i.d. There was an increase in the maximum plasma isofezolac concentration from 2.44 to 3.38 micrograms X ml-1 when probenecid was given. The AUC of isofezolac in plasma increased from 6.73 to 11.28 micrograms X h X ml-1. After the last dose in a 7 day treatment with 40 mg isofezolac t.i.d., there was an increase in the maximum plasma isofezolac level from 2.84 to 4.96 micrograms X ml-1 when probenecid was given. The rate of absorption of isofezolac was not affected. An increase in the AUC of isofezolac in plasma was observed from 11.74 to 26.34 micrograms X h X ml-1. The major effect of probenecid on isofezolac metabolism was a 50% reduction in total isofezolac (free + conjugates) excreted inurine. Because of this interaction, patients given isofezolac combined with probenecid will have a higher steady-state plasma level of isofezolac than when probenecid is not administered.