Comparative Pharmacokinetics of the Anticoagulant Effect of Coumarin Drugs in Man and Rat
The coumarin anticoagulants are a particularly interesting group of drugs for pharmacokinetic study because their concentration in plasma or serum and their anticoagulant effect can be readily measured. In addition, these drugs are widely used and subject to many clinically important interactions with other drugs. Our interest in the pharmacokinetics of warfarin and dicumarol was stimulated largely by the classical investigations by O’Reilly et al. (1970) and by a collaborative study with him seven years ago (O’Reilly et al., 1966). We became very intrigued by the unusual dose-dependence of the kinetics of dicumarol elimination in man (O’Reilly et al., 1964) and by the fact that the temporal pattern of the anticoagulant effect of the coumarin drugs appears to lag considerably behind the concentrations of these drugs in the plasma. Since nonlinear kinetics of drug elimination (Levy, 1968; Levy et al., 1972; Tsuchiya and Levy, 1972) and kinetics of drug action (Levy, 1966; Levy, 1973) are among our major areas of research, it was only natural to focus on both of these aspects as they pertain to the coumarin anticoagulants. The research on the dose-dependent kinetics of dicumarol elimination has been described in a series of six publications from 1968 (Nagashima et al., 1968) to 1969 (Levy and Nagashima, 1969) and has now been expanded to a general consideration of the role of product inhibition in the dose-dependent elimination of drugs that are subject to hydroxylation (Levy et al., 1972).
KeywordsWarfarin Dose Racemic Mixture Anticoagulant Effect Individual Enantiomer Coumarin Anticoagulant
Unable to display preview. Download preview PDF.
- Levy, G., 1966, Clin. Pharmacol. Therap. 7: 362.Google Scholar
- Levy, G., 1968, in: Importance of Fundamental Principles in Drug Evaluation (Tedeschi, D. H., and Tedeschi, R. E., eds.) Raven Press, New York.Google Scholar
- Levy, G., 1973, Proc. Fifth Intern. Congr. Pharmacol., 3: 34.Google Scholar
- Levy, G., Ashley, J. J., Jähnchen, E., and Perrier, D., 1972, Abstracts, 13th Nat. Mtg. A.Ph.A. Acad. Pharm. Sci. 2: 179.Google Scholar
- Levy, G., O’Reilly, R. A., Aggeler, P. M., and Keech, G. M., 1970, Clin. Pharmacol, & Therap. 11: 372.Google Scholar
- Levy, G., Tsuchiya, T., and Amsel, L. P., 1972, Clin. Pharmacol. Therap. 13: 258.Google Scholar
- Nagashima, R., O’Reilly, R. A., and Levy, G., 1969, Clin. Pharmacol. Therap. 10: 22.Google Scholar
- O’Reilly, R. A., 1973, Clin. Res. 21: 197.Google Scholar
- O’Reilly, R. A., Aggeler, P. M., and Leong, L. S., 1964, Thromb, Diath. Haemorrhag. 11: 1.Google Scholar
- O’Reilly, R. A., and Levy, G., 1970, Clin. Pharmacol. Therap. 11: 378.Google Scholar
- Wingard, L. B., Jr., and Levy, G., 1972, J. Pharmacol. Exp. Therap., 184: 253.Google Scholar