Pharmacokinetics and Pharmacodynamics of Warfarin at Steady State

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 1979 Sep 1

PMID 497091

Citations 17

Authors

P A Routledge

P H Chapman

D M Davies

M D Rawlins

Affiliations

Soon will be listed here.

Abstract

1 The relationship between warfarin dose, total and free plasma warfarin concentration, and anticoagulant effect was examined at several steady-state levels in fifteen patients during withdrawal of warfarin therapy. 2 Total plasma clearance was significantly correlated with the free fraction in plasma (r=0.955). 3 There was an age related decline in the dose of warfarin, and in the total and free plasma warfarin concentrations required to produce the same anticoagulant effect. However, neither total nor free plasma warfarin clearances varied with age. 4 Individual patients' log concentration-effect relationships were linear above a prothrombin ratio of 1.2 and there was a significant correlation (r=-0.586) between the slope and the free fraction of warfarin in plasma. It is suggested that plasma protein binding may reflect the interaction between warfarin and its effector site in the hepatocyte.

Citing Articles

Influence of adult age on the total and free clearance and protein binding of (R)- and (S)-warfarin.

Jensen B, Chin P, Roberts R, Begg E Br J Clin Pharmacol. 2012; 74(5):797-805.

PMID: 22380743 PMC: 3495144. DOI: 10.1111/j.1365-2125.2012.04259.x.

Free drug metabolic clearance in elderly people.

Butler J, Begg E Clin Pharmacokinet. 2008; 47(5):297-321.

PMID: 18399712 DOI: 10.2165/00003088-200847050-00002.

Prediction of the international normalized ratio and maintenance dose during the initiation of warfarin therapy.

Vadher B, PATTERSON D, Leaning M Br J Clin Pharmacol. 1999; 48(1):63-70.

PMID: 10383562 PMC: 2014877. DOI: 10.1046/j.1365-2125.1999.00967.x.

The influence of age, liver size and enantiomer concentrations on warfarin requirements.

Wynne H, Cope L, Kelly P, Whittingham T, Edwards C, Kamali F Br J Clin Pharmacol. 1995; 40(3):203-7.

PMID: 8527280 PMC: 1365098.

Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin.

Chan E, McLachlan A, Pegg M, Mackay A, Cole R, Rowland M Br J Clin Pharmacol. 1994; 37(6):563-9.

PMID: 7917775 PMC: 1364816. DOI: 10.1111/j.1365-2125.1994.tb04305.x.

References

Gibaldi M, McNamara P . Tissue binding of drugs. J Pharm Sci. 1977; 66(8):1211-2. DOI: 10.1002/jps.2600660846. View

Yacobi A, Levy G . Protein binding of warfarin enantiomers in serum of humans and rats. J Pharmacokinet Biopharm. 1977; 5(2):123-31. DOI: 10.1007/BF01066216. View

Shepherd A, Hewick D, Moreland T, Stevenson I . Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977; 4(3):315-20. PMC: 1429084. DOI: 10.1111/j.1365-2125.1977.tb00719.x. View

Yacobi A, Levy G . Comparative pharmacokinetics of coumarin anticoagulants XXVIII: Predictive identification of rats with relatively steep serum warfarin concentration-anticoagulatnt response characteristics. J Pharm Sci. 1977; 66(1):145-6. DOI: 10.1002/jps.2600660145. View

Mitchell A . Smoking and warfarin dosage. N Engl J Med. 1972; 287(22):1153-4. View

Wagner J, NORTHAM J, ALWAY C, CARPENTER O . Blood levels of drug at the equilibrium state after multiple dosing. Nature. 1965; 207(5003):1301-2. DOI: 10.1038/2071301a0. View

Lewis R, TRAGER W, Chan K, Breckenridge A, Orme M, Roland M . Warfarin. Stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest. 1974; 53(6):1607-17. PMC: 302656. DOI: 10.1172/JCI107711. View

Breckenridge A, Orme M . Kinetics of warfarin absorption in man. Clin Pharmacol Ther. 1973; 14(6):955-61. DOI: 10.1002/cpt1973146955. View

Rawlins M, Collste P, Frisk-Holmberg M, Lind M, Ostman J, Sjoqvist F . Steady-state plasma concentrations of alprenolol in man. Eur J Clin Pharmacol. 1974; 7(5):353-6. DOI: 10.1007/BF00558205. View

10.

Levy G, Yacobi A . Letter: Effect of plasma protein binding on elimination of warfarin. J Pharm Sci. 1974; 63(5):805-6. DOI: 10.1002/jps.2600630539. View

11.

AGGELER P, OReilly R . The pharmacological basis of oral anticoagulant therapy. Thromb Diath Haemorrh Suppl. 1966; 21:227-56. View

12.

Yacobi A, Udall J, Levy G . Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect. Clin Pharmacol Ther. 1976; 19(5 Pt 1):552-8. DOI: 10.1002/cpt1976195part1552. View

13.

Lewis R, Ilnicki L, Carlstrom M . The assay of warfarin in plasma or stool. Biochem Med. 1970; 4(5):376-82. DOI: 10.1016/0006-2944(70)90065-7. View

14.

Nagashima R, OReilly R, Levy G . Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin Pharmacol Ther. 1969; 10(1):22-35. DOI: 10.1002/cpt196910122. View

15.

OReilly R . Studies on the coumarin anticoagulant drugs: interaction of human plasma albumin and warfarin sodium. J Clin Invest. 1967; 46(5):829-37. PMC: 297084. DOI: 10.1172/JCI105582. View