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Biomedical subjects

M Lesne

Publications and source records attributed to M Lesne.

At least 91 records · Page 5Linked to original sources
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Hepatic clearance of gitoxin. Metabolism and biliary excretion by rabbit isolated liver.

After in vitro perfusion of rabbit isolated liver with an emulsion of perfluorocarbon containing [3H]gitoxin, the radioactivity in the liver and in the bile was the sum of that contained in a volatile fraction (tritiated water due to metabolism of gitoxin) and that contained in a nonvolatile fraction (gitoxin and its metabolites). This fraction was divided, by differential extraction, into two groups: liposoluble (dichloromethane soluble) compounds, including unchanged gitoxin and lipophilic metabolites (amounting to 50% in the liver and to 5% in the bile), and hydrosoluble (dichloromethane insoluble) metabolites (50% in the liver, 95% in the bile). Three types of metabolites were found in the hydrosoluble fraction. One type was sensitive to beta-glucuronidase and arylsulfatase hydrolysis, a second type was insensitive to enzymatic hydrolysis but sensitive to acid hydrolysis, and a third type was insensitive to both enzymatic and acid hydrolysis. The liposoluble compounds and the conjugates sensitive to enzymatic hydrolysis were analyzed by reversed phase high performance liquid chromatography and found to comprise a wide variety of metabolites. The present study demonstrates that gitoxin uptake by the liver is followed by a fast and extensive metabolism to highly polar metabolites that are rapidly excreted into the bile.

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Metabolism and excretion in bile of SC4453, a new semi-synthetic derivative of digoxin following an i.v. bolus injection in the guinea-pig.

After a single bolus injection of tritiated SC4453 in the guinea-pig, 36% of the dose was excreted in the bile during the first 6 hours after administration. Solvent partition has shown that 88% of the total radioactivity excreted was soluble in dichloromethane (DCM). Thin layer chromatography analysis of the DCM soluble fraction has shown that SC4453 was mainly excreted unchanged in the bile. Enzymatic hydrolysis of the water soluble fraction has shown that the main partner of conjugation was SC4453 itself. This study has demonstrated a significant enterohepatic circulation for SC4453, suppression of which modified the pharmacokinetic parameters of SC4453 in the guinea-pig. The half-life of elimination decreases from 4.2 hours to 3.22 hours and the volume of distribution (Vdarea) was equal to 2680 ml/kg versus 3692 ml/kg for normal guinea-pig.

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Importance of the urinary excretion in the total elimination of SC4453 in the guinea-pig.

Administration of SC4453 (30 micrograms/kg) in the guinea-pig increases the rate of urinary excretion from 35 ml/kg/24 h to 55 ml/kg/24 h. Ligature of ureters modifies parameters of SC4453 ; t 1/2 beta increases from 4.2 h to 5.6 h and the body clearance diminishes from 622 ml/h/kg (normal guinea-pig) to 530 ml/h/kg in the ligatured ureters guinea-pig. Analysis of the radioactive material excreted in the urine after administration of tritiated SC4453 shows that 58.4% is dichloromethane (DCM) soluble and 41.6% is water soluble. Thin layer chromatography (TLC) of the DCM soluble fraction shows that 74.0% is unchanged SC4453 . After enzymatic hydrolysis of the water soluble fraction, it is shown that 28% is again extractable by DCM of which 57% consists of unchanged SC4453 which is therefore the main partner of conjugated products. Following an i.v. injection of tritiated SC4453 , only 17% of the dose was recovered in urine, against 14% after an intragastric administration. Gastro-intestinal absorption of SC4453 was estimated to be 82.2%.

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Comparison of the pharmacokinetic parameters of digoxin and SC4453 a digoxin analogue, following a single bolus i.v. dose and following an infusion preceeded by an i.v. loading dose in the guinea-pig.

The pharmacokinetics of SC4453 was studied in comparison with digoxin both after an intravenous injection and an intravenous infusion following an intravenous bolus injection of a loading dose in the guinea-pig. Doses of 7.8 micrograms/kg for digoxin and 30 micrograms/kg for SC4453 were administered as a bolus. The solutions were prepared from a stock solution (10(-3) M in ethanol-water 7:3) diluted with 0.9% saline. The half lives (t 1/2 beta) for digoxin and SC4453 were 8.4 h and 4.2 h respectively. The apparent volumes of distribution (V1) were respectively 11.4 l/kg and 3.7 l/kg. Using these parameters, an I.V. infusion was administered after an initial bolus injection of a properly calculated loading dose (D* = CpssV1). The perfusion constant K was calculated from the equation: K = CpssV1ke.

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PubMedDate not supplied

[Hepatic clearance of drugs. Physiological and pharmacokinetic considerations].

The aim of the first part of this work is to present elements of hepatic cytology and physiology in order to demonstrate the organisation of the liver for the metabolisation of drugs: the cytology of hepatocytes, their arrangement in the parenchyma, the hepatic microvascularisation, the distribution of the metabolic reactions in the hepatic acinus and the structure of the biliary tract involved in the elimination of some metabolites. 2. The second part is devoted to the concept of hepatic clearance. A few considerations are presented about physiological aspects (hepatic uptake), followed by a more extensive chapter about pharmacokinetics. The following points are explained: mathematical terms of clearance, physiological models, hepatic first-pass effect, influence of the hepatic clearance on half-life of a drug and area under the curve of concentration versus time, the use of clearance or half-life as index of hepatic metabolism and a classification of the drugs in correlation with their hepatic clearance. 3. The conclusions present some contradictions and unresolved points persisting, at the present time, in the hepatic clearance theories and propose new approaches for future investigations.

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