The pharmacodynamics of i.v. and subcutaneous (s.c.) tinzaparin sodium compared with heparin in healthy volunteers were studied. A randomized, open-label, five-treatment, five-period-crossover study with a Latin square design was performed in 30 healthy men to estimate tinzaparin pharmacodynamics (anti-Xa and anti-IIa activities) after single-dose i.v. and s.c. administration, to evaluate absolute bioavailability, to determine the effect of a preservative (benzyl alcohol), to evaluate the dose-activity relationship, and to compare tinzaparin with unfractionated heparin. Treatments were (1) heparin 5,000 units s.c., (2) tinzaparin 4,500 anti-Xa IU without preservative s.c., (3) tinzaparin 4,500 anti-Xa IU without preservative i.v., (4) tinzaparin 12,250 anti-Xa IU with preservative s.c., and (5) tinzaparin 4,500 anti-Xa IU with preservative s.c. Blood samples for the measurement of anti-Xa and anti-IIa activities were drawn over 24 hours. Anti-Xa and anti-IIa activities were determined by chromogenic methods; data were analyzed by using a noncompartmental approach. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2.04 L/hr. The volume of distribution was 3.1-5.0 L, suggesting that the molecular entities responsible for anti-Xa and anti-IIa activities are confined to the intravascular space. Mean peak anti-Xa activity occurred three to four hours after s.c. injection, independent of the dose. The mean half-life of anti-Xa activity after s.c. injection ranged from 3.41 to 4.13 hours and was independent of the dose. The mean absolute bioavailability of s.c. tinzaparin was 86.7%. Intersubject pharmacodynamic variability was low for tinzaparin compared with heparin. Benzyl alcohol did not affect tinzaparin pharmacodynamics. A clear dose-activity relationship was seen for the two fixed doses of tinzaparin (12,250 and 4,500 IU). Single doses of tinzaparin were safe and well tolerated after administration by either route. The anti-Xa profile of tinzaparin supports the pharmacodynamic superiority of low-molecular-weight heparins over standard i.v. heparin administration. This pharmacodynamic study in healthy volunteers indicates that s.c. tinzaparin sodium was well absorbed; the presence of a preservative, benzyl alcohol, did not affect the activity of tinzaparin; and tinzaparin activity is dose-related.