Pharmacokinetics of warfarin in rats: role of serum protein binding and tissue distribution
The purpose of this study was to explore the role of serum protein binding and tissue distribution in the non-linear pharmacokinetics of warfarin in rats. The first phase of the research was an attempt to elucidate the causes of intersubject differences in serum protein binding of warfarin in rats. It was found that the distribution of S-warfarin between blood and liver, kidneys, muscle, or fatty tissue was non-linear. Based on the tissue distribution data obtained, a physiologically-based pharmacokinetic model was developed to describe the time course of S-warfarin concentrations in the serum and tissues of rats. The proposed model was able to display the dose-dependent pharmacokinetics of warfarin in rats. Namely a lower clearance and a smaller apparent volume of distribution with increasing dose, which appear to be due to the presence of capacity-limited, high-affinity binding sites for warfarin in various tissues. To determine if the binding of warfarin to the high-affinity binding sites in the liver of rats is reversible, concentrations of S-warfarin in the liver and serum of rats were monitored for a very long time after an intravenous injection of a 1 mg/kg dose. In another study in rats, non-radioactive warfarin was found to be able to displace tissue-bound C/sup 14/-warfarin which was administered about 200 hours before the i.v. injection of the non-radioactive warfarin, showing that the binding of warfarin to the high-affinity binding sites in the body is persistent and reversible.
- Research Organization:
- State Univ. of New York, Buffalo (USA)
- OSTI ID:
- 5151414
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
ADIPOSE TISSUE
AFFINITY
ANIMAL TISSUES
ANIMALS
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MATERIALS
BLOOD
BODY
BODY FLUIDS
CARBON 14 COMPOUNDS
CHEMICAL BONDS
CLEARANCE
CONNECTIVE TISSUE
COUMARIN
DIGESTIVE SYSTEM
DISTRIBUTION
DOSE-RESPONSE RELATIONSHIPS
ESTERS
GLANDS
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
KIDNEYS
KINETICS
LABELLED COMPOUNDS
LACTONES
LIVER
MAMMALS
MATERIALS
MATHEMATICAL MODELS
MUSCLES
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PYRANS
RATS
REACTION KINETICS
RODENTS
TISSUE DISTRIBUTION
TISSUES
TRACER TECHNIQUES
VERTEBRATES