Pharmacokinetics of Warfarin Following Intravenous Administration to Man^[*]

Summary

Nine sets of plasma concentration, time data, observed following rapid intravenous injection of sodium warfarin to human subjects, were fit well by the equation appropriate to the two compartment open model. The average value of the forward distribution rate constant (K₁) was 0.700 h^-1 (standard deviation 0.623 h^-1); the average value of the reverse distribution rate constant (K_-1) was 1.09 h^-1 (S.D. 0.583 h^-1); the average value of the loss rate constant (K₂) was 0.0362 h^-1 (S.D. 0.015 h^-1); and the average volume of the inner compartment, of which plasma is assumed to be representative, was 4.72 1 (S.D. 0.989 1) corresponding to an average of 7.18% of body weight (S.D. 1.46). These data indicate that in the dose range studied, 50 to 600 mg of sodium warfarin, there is no evidence of dose-dependent kinetics of warfarin in man.

• References

• 1 O’Reilly R. A, Aggeler P. M, Leong L. S. Studies on the Coumarin Anticoagulant Drugs: A comparison of the pharmacodynamics of dicoumarol and warfarin in man. Thrombos. Diathes. haemorrh. (Stuttg.) 11: 1 1964;
• 2 Nagashima R, Levy G. Comparative Pharmacokinetics of Coumarin in Anticoagulants V: kinetics of warfarin elimination in the rat, dog and rhesus monkey compared to man. J. Pharm. Sci 58: 845 1969;
• 3 Nagashima R, O’Reilly R. A, Levy G. Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin. Pharmacol. Therap 10: 22 1969;
• 4 Levy G, O’Reilly R. A, Aggeler P. M, Keech G. M. Pharmacokinetic analysis of the effect of barbiturate on the anticoagulant action of warfarin in man. Clin. Pharmacol. Therap 11: 372 1970;
• 5 O’Reilly R. A, Aggeler P. M, Hoag M. S, Leong L. Studies on the coumarin anticoagulant drugs: the assay of warfarin and its biologic application. Thrombos. Diathes. haemorrh. (Stuttg.) 08: 82 1962;
• 6 The program NONLIN was kindly supplied by Dr. C.M. Metzler. The Upjohn Company; Kalamazoo, Michigan.:
• 7 Wagner J. G, Welling P. G, Lee K. P, Walker J. S, Ho N. F. H, Chadiha J. H. M. Studies on thein vivo andin vitro availability of some commercial warfain tablets. J. Pharm. Sci. submitted July 1, 1970
• 8 Reeve E. B. The plasma albumin system. A first attempt at a kinetic description in dynamic clinical studies with radioisotopes. Proceedings of a symposium held at the Oak Ridge Institute of Nuclear Studies, October 21-25, 1963. U. S. Department of Commerce TID 7678, Office of Technical Services, U.S. Department of Commerce. Washington, D.C: 20330, 1964: 445-472.