The disposition of the enantiomers of warfarin following chronic administration to rats: relationship to anticoagulant response.
A model of chronic anticoagulation has been used to investigate the whole liver and subcellular disposition of the individual enantiomers of warfarin in the Wistar rat in relation to anticoagulant response. Consistent pharmacodynamic responses were achieved by dosing daily with R-warfarin (0.4, or 0.8 mg kg-1 day-1 i.p.) or S-warfarin (0.1 mg kg-1 day-1 i.p.). After the administration of increasing doses of R-warfarin, prothrombin times were dose-dependent (16.3 +/- 0.5 s, 0.1 mg kg-1 day-1; 21.6 +/- 1.7 s, 0.4 mg kg-1 day-1; 55.1 +/- 9.0 s, 0.8 mg kg-1 day-1; results all measured 24 h after the final dose). Increasing doses of R-warfarin also produced increases in plasma, whole liver, and cytosolic concentrations of warfarin. However, there were no significant differences between the microsomal concentrations of R-warfarin in the three groups. The dose of S-warfarin required to produce a consistent and significant increase in the prothrombin time was four-fold lower than the dose of R-warfarin required to cause a similar effect. Plasma concentrations of S-warfarin were not significantly different from those seen after 0.4 mg kg-1 day-1 R-warfarin. Whole liver and cytosolic concentrations of the S-enantiomer were lower than those observed after a dose of 0.4 mg kg-1 day-1 R-warfarin. However, consistent with microsomal concentrations following increasing doses of R-warfarin, there was no significant difference between microsomal concentrations of R(+)- and S(-)-warfarin.(ABSTRACT TRUNCATED AT 250 WORDS)
Pratt
S K
SK
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Winn
M J
MJ
Park
B K
BK
D000818:Animals; D000925:Anticoagulants; D002851:Chromatography, High Pressure Liquid; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D011517:Prothrombin Time; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology
D000925:Anticoagulants; D014859:Warfarin