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Heparin kinetics were determined in four normal subjects, each of whom received three different doses (25, 50, and 75 units/kg body weight) by intravenous injection. Multiple blood samples were collected after each dose and each plasma sample was assayed for heparin activity using three different assay methods. Two of these assays are based on coagulation tests, i.e., activated partial thromboplastin time and thrombin time, while the third is based on chemical neutralization of heparin using hexadimethrine bromide. Heparin kinetics showed pronounced dose-dependent changes, irrespective of the assay method used, which were characterized by increasing biologic half-life and decreasing total clearance (Cl) with increasing dose. No changes were noted in apparent volume of distribution (Vd). This data also showed that there were differences in kinetic parameters of heparin depending on the assay method. In general, values for total Cl and apparent Vd based on chemical neutralization were approximately 1.5 to 2.0 times these parameters based on coagulation tests. We conclude that the immediate mechanism of the dose-dependent heparin kinetics is decreasing total clearance with increasing dose and suggest that in vivo activation of the anticoagulant properties of heparin may explain the assay-dependent kinetics.

Six normal subjects (three men and three women) took 200 mg sulfinpyrazone in two oral preparations, a capsule and a suspension. Plasma and urine levels of sulfinpyrazone and the sulfide, p-hydroxy, and sulfone metabolites were measured over three days. The plasma sulfinpyrazone/time concentration profiles indicated a postabsorptive biexponential decline with a mean terminal half life (t1/2) of 299 +/- 107 min. There was intersubject variation in the formation of the metabolites, the greatest being with the sulfide metabolite. Mean t1/2 of the sulfide metabolite was 659 +/- 192 min. The apparent fraction of sulfinpyrazone absorbed was 0.93 +/- 0.24 and the free fraction in plasma was 1.26 +/- 0.04%. Since the sulfide metabolite has a more potent antiplatelet effect and its formation in normal subjects is variable, direct administration of the sulfide may provide a more predictable antithrombotic effect in patients.

The kinetics of the antiplatelet drug dipyridamole were studied in six normal subjects (three men and three women) who were ages 22 to 34 yr old. Each received 20 mg IV and four also took a 50-mg oral dose. Blood samples were collected after each dose for a period of 3 days and concentrations of dipyridamole were measured by a sensitive and specific high-performance liquid chromatographic assay. Concentrations after the intravenous dose showed a triexponential decline with a terminal half-life of 11.6 +/- 2.2 hr (x +/- SD). Total plasma clearance was 8.27 +/- 1.82 1/hr and the apparent volume of distribution was 141 +/- 51 1. Concentrations rose 6 to 10 hr after intravenous dipyridamole in each female subject, but not in the male subjects. Dipyridamole blood/plasma concentration ratio changed from an average of 0.7 over the first hour to 1.2 after 5 hr after the intravenous dose. There was an absorption lag time ranging from 34 to 75 min after the oral dose; concentrations peaked at about 2 to 2.5 hr after the dose. The percentage of unbound drag in plasma was 0.88 +/- 0.24%. Systemic availability of the end oral dose was 43 +/- 13%. These results suggest widely varying concentrations in patients receiving the drug, and raise questions about the current clinical practice of using empirical dosage schedules.