Biliary excretion of 14C-dicumarol or its metabolic products in the rat

Husain, S.; Wosilait, Walter D.; Eisenbrandt, L.L.

doi:10.1016/0024-3205(71)90217-7

Life Sciences

1971

DOI: 10.1016/0024-3205(71)90217-7

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Biliary excretion of 14C-dicumarol or its metabolic products in the rat

S. Husain

Walter D. Wosilait

L.L. Eisenbrandt

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1971

1983

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Cited by 6 publications

(2 citation statements)

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“…None of these metabolites has been identified, and it is not known whether any possesses physiological activity (10). While biliary excretion has been recognized as a major pathway for elimination of dicumarol, few studies have been made on bile (8,9,11,12), and in only two of these (8,9) were the metabolites separated.The most extensive study (7) of the structure of a metabolite concerned a metabolite isolated from the feces of rats and designated as B055 to signify its mobility of 0.55 in the paper chromatographic system of n-butanol-3 M ammonia (1:l). This metabolite contained a hydroxy group in position 7 of one coumarin ring; it was neither a glucuronide nor identical with 7-hydroxydicumarol(II).…”

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confidence: 99%

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Determination of Dicumarol Metabolites in Bile of Rats

Conway

Lee

Neufeld

1975

Journal of Pharmaceutical Sciences

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mentioning

confidence: 99%

mentioning

confidence: 99%

Determination of Dicumarol Metabolites in Bile of Rats

Conway

Lee

Neufeld

1975

Journal of Pharmaceutical Sciences

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The effect of hepatic uptake on the disappearance of warfarin from the plasma of rats: A kinetic analysis

Covell¹,

Abbrecht

Berman³

1983

Journal of Pharmacokinetics and Biopharmaceutics

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To quantify the effects of the liver on the dose dependence of plasma warfarin clearance, an equal number of normal and functionally hepatectomized rats received an intravenous bolus of either 0.01, 0.1, or 1.0 mg/kg body weight of radiolabelled sodium warfarin. Serial samples of plasma and bile collected from each rat during the 1 hr experiment and of hepatic tissue collected at the end of the experiment were analyzed for radioactivity. The disappearance of warfarin from the plasma of hepatectomized rats was not dose dependent and suggested that the apparent dose dependency of plasma warfarin clearance is primarily the result of warfarin's interaction with hepatic tissue. The disappearance of warfarin from the plasma of normal rats was dose dependent with higher doses being cleared less rapidly. This dose dependence, however, was not reflected in the rate of biliary excretion of warfarin's metabolites, which did not show saturation over this dosage range. These results were used to develop a multicompartmental model of warfarin's pharmacokinetics. Plasma warfarin data collected from the hepatectomized rats were used to develop the extrahepatic components of the model, which was then expanded to include hepatic tissues based on data collected from normal rats. To simultaneously fit the plasma, biliary, and hepatic data required that at least two classes of hepatic tissue exchange warfarin with plasma. One tissue exhibited Michaelis-Menten saturation kinetics with Kd and maximum capacity estimated at 1.49E - 3 micrograms/ml and 2.72 micrograms/ml, respectively. The second class exhibited linear exchange kinetics with free plasma warfarin. Warfarin's association with the second class of hepatic tissue leads to its metabolic elimination. Consistent with our experimental findings, the rate of warfarin elimination from the plasma into the bile was linearly related to plasma warfarin concentration. Thus the single hepatic exchange nonlinearly was necessary and sufficient to account for the apparent dose dependency in plasma warfarin's pharmacokinetics. These results suggest that over the range of doses studied, the apparent dose dependent differences in the plasma warfarin concentration profile can be accounted for by saturable hepatic uptake. This mechanism, however, is not related to warfarin's metabolic enzymes, which do not show saturation in the dosage range studied.

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An autoradiographic study of the distribution and excretion of 14C-dicoumarol in the rat

Maines

Wosilait

1971

Comparative and General Pharmacology

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Biliary excretion of 14C-dicumarol or its metabolic products in the rat

Cited by 6 publications

References 3 publications

Determination of Dicumarol Metabolites in Bile of Rats

Determination of Dicumarol Metabolites in Bile of Rats

The effect of hepatic uptake on the disappearance of warfarin from the plasma of rats: A kinetic analysis

An autoradiographic study of the distribution and excretion of 14C-dicoumarol in the rat

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