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Hepatic uptake and storage of warfarin. The relation with the target enzyme vitamin K 2,3-epoxide reductase

Journal Article · · J. Pharmacol. Exp. Ther.; (United States)
OSTI ID:5362811
;

The mechanisms of the reported dose-dependent warfarin pharmacokinetics were investigated using (/sup 14/C)warfarin. When administered in microdoses (9 micrograms i.v.) to rats (male Wistars, 270-300 g), a steep distribution phase (T1/2 = 0.25 hr) was followed by a relatively slow beta-phase (T1/2 = 40 hr). The observed volume of distribution was 390 ml. This pharmacokinetic behavior contrasted highly with the one seen for higher (greater than 0.2 mg/kg) doses (unlabeled) warfarin; volume of distribution = 45 ml, T1/2 = 12.5 hr. If a macrodose (0.2 mg/kg) preceded (16 hr) the microdose, normal pharmacokinetics were observed for the latter, suggesting a saturable deep compartment. The administration of 4-hydroxycoumarins (i.e., acenocoumarol, phenprocoumon and warfarin) after the microdose of (/sup 14/C)warfarin was in its beta-phase caused a rapid rise of plasma (/sup 14/C)warfarin indicating (/sup 14/C)warfarin to be displaced from the deep compartment. The rate of appearance of (/sup 14/C)warfarin was 0.3 hr-1 irrespective the 4-hydroxycoumarin used. The hepatic distribution of (/sup 14/C)warfarin was investigated and the effect of a displacer thereupon. Fifty-three hours after the (/sup 14/C)warfarin administration, the liver contained about 40% of the dose; 45% of it was bound to microsomes. The administration of acenocoumarol (0.2 mg/kg) at 48 hr, halved the liver content. (/sup 14/C)warfarin was redistributed from microsomes (-65%) and from the 10,000 X g pellet (-65%) into the cytosol (+260%) and the plasma (+320%). Microsomal bound (/sup 14/C)warfarin in vitro could not be washed out or be displaced unless dithiothreitol (50 mM) was included in the washing buffers.

Research Organization:
Univ. of Limburg, Maastricht, The Netherlands
OSTI ID:
5362811
Journal Information:
J. Pharmacol. Exp. Ther.; (United States), Journal Name: J. Pharmacol. Exp. Ther.; (United States) Vol. 243:3; ISSN JPETA
Country of Publication:
United States
Language:
English

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Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BIOCHEMICAL REACTION KINETICS
BODY
CARBON 14 COMPOUNDS
CELL CONSTITUENTS
COUMARIN
DIGESTIVE SYSTEM
DISTRIBUTION
DOSE-RESPONSE RELATIONSHIPS
ENZYME ACTIVITY
ENZYMES
ESTERS
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROXYLASES
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
LACTONES
LIVER
MAMMALS
METABOLISM
MICROSOMES
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANOIDS
ORGANS
OXIDOREDUCTASES
PYRANS
RATS
REACTION KINETICS
RODENTS
TISSUE DISTRIBUTION
TRACER TECHNIQUES
UPTAKE
VERTEBRATES