[Protein binding of fenpentadiol-14C (2-méthyl-4-p-chlorophényl-2,4-pentane-diol) in vivo and in vitro (author's transl)]. / Etude in vivo et in vitro des liaisons protéiniques du fenpentadiol-14C (2-méthyl-4-p-chlorophényl-2,4-pentane-diol).

The binding of 14C-fenpentadiol to plasma proteins of different species in vivo and in vitro was studied using equilibrium dialysis. In vivo, the binding rate, in rat, was found to be 30%. In the pig, this rate varied as a function of time from 10.8% 15 minutes after drug administration to 20.4% 6 hours later. In vitro, the binding rate was found to be a function of the drug concentration and ranged from 57 to 36% at concentrations of from 0.4 to 11 micrograms/ml. No significant differences were observed between the two species. In human plasma, the in vitro binding rate was found to range from 34 to 18.4% for concentrations of 11 to 200 micrograms/ml. Under the same conditions, but using 10 mg of human albumin incubated in varying concentrations of the drug (50 to 800 micrograms/ml), the binding rate ranged from 8.4 to 4%. The binding rate seemed also to be a function of the pH of the medium with the pH of 11 yielding a maximum binding rate. Scatchard analysis of the in vitro human albumin data gave the following values: K = 4.7 X 10(3) M-1, n = 1.5. When human alpha-globulin was used, the protein binding values varied from 9.1 to 4.3% at drug concentrations from 50 to 40 micrograms/ml. When human beta- and gamma-globulins were used, no binding was found to occur. In vitro, incubation of the drug in whole blood of either rat or pig gave a value of 20% drug fixed in erythrocytes. In vivo, in the rat, this value was found to be 60%.

Pharmacokinetic study of maleate acid of 2-(N,N-dimethylaminoethanol-14C1)-cyclohexylpropionate (cyprodenate) and of N,N-dimethylaminoethanol-14C1 in animals.

The localization, distribution, and elimination of maleate acid 2-(N,N-dimethylaminoethanol-14C1)-cyclohexylpropionate (14C-cyprodenate, Actebral) was studied in rats and pigs. Beside this, dimethylaminoethanol-14C (DMAE) was also administered to rats enabling a comparison of the pharmacokinetics of the two 14C-labelled molecules to be made. The study of the localization by autoradiography and the study of the quantitative distribution of the radioactivity showed that cyprodenate, a psychotonic drug, diffused more rapidly than DMAE through the hemo-encephalic barrier. However, it was also observed that the radioactivity found in the brain rises continually as a function of time, regardless of the product administered. The two labelled products were primarily excreted in the urine (30-35 per cent of the dose in 72 h in rats and 6 per cent of the dose in 48 h in pigs) following oral administration of cyprodenate. Radioactivity found in the feces was practically nil and in rats the biliary elimination of the drug was very weak. Thus, whichever animal is used, it was found that 14C-cyprodenate is totally absorbed. Radioactivity expired as 14CO2 was negligible (around 1 per cent of the administered dose in 8 h), however, this value increases as a function of time, becoming 4 per cent in 24 h. In rats the maximum radioactivity in the blood was found at 45 min to 1 h after oral administration of 14C-cyprodenate. These values decrease slowly until 3 h when they begin to increase again. The rising of the blood level values is practically the same for pigs, the maximum being attained at 1 h. Therefore, whatever route of administration, whichever dose or animal, we always found a progressive elevation of the protein binding to the plasma proteins for these two labelled products in vivo.

Pharmacokinetic study of maleate acid of 2-(N,N-dimethylaminoethanol-14C1)-cyclohexylpropionate (cyprodenate) and of N,N-dimethylaminoethanol-14C1 in animals.

The study of the biotransformation of 2-(N,N-dimethylaminoethanol)-cyclohexylpropionate-meleate acid (cyprodenate, Actebral), a psychotonic brain stimulant, was carried out on two species of animals (rats and pigs) with the aid of 14C-labelled molecules. Following i.v. administration in rats it was found that 14C-cyprodenate diffuses very rapidly to the principal organs (liver, brain, kidneys) preceding a hydrolysis which gives 14C-dimethylaminoethanol (DMAE). The latter undergoes N-oxidation but the major portion of DMAE goes directly into the metabolic cycle of the phospholipids up to the formation of 14C-choline, as shown in the metabolic scheme proposed by the authors that identifies the principal labelled intermediaries: 14C-phosphoryl-DMAE (P-DMAE), 14C-glycerophosphatidyl-N,N-dimethylethanolamine (GP-DMAE), 14C-glycerophosphatidyl-choline (GP-choline). Similar results were found with the oral administration of 14C-cyprodenate in pigs, thus showing a more intense participation of the product at the level of the intermediary metabolism of phospholipids, precursors of choline.

[Liver extract effect on liver microsomal system and on an experimental model of intoxication]. / Effet d'un extrait de foie sur le système microsomal hépatique et sur un modèle d'intoxication expérimentale.

A lyophilized liver extract (FLR) lengthens hexobarbital action in control rats ; it decreases slightly the induction of hepatic microsomal enzymes and normalizes diphenylhydantoin protection against electroshock seizure in phenobarbital-treated animals ; in the event of a CC14 intoxication, this extract reestablishes values close to normal for mebubarbital metabolism in mice and for BSP clearance in rats. FLR could act in regularizing drug metabolism.

Pharmacokinetics of 14C-N-N'-dicyclopropyl-methyl-piperazine-dichlorhydrate. 1st Communication: balance of elimination, plasma and blood kinetics, metabolism in rats.

N-N'-Dicyclopropyl-methyl-piperazine-dichlorhydrate (Ino 2628-CZ) is a novel inotropic compound. The absorption, distribution, excretion and metabolism of radiochemically labelled 14C-Ino 2628-CZ has been studied in male and female rats after intravenous and oral administration. The compound was mainly excreted during the first 24 h after both administrations, although traces of radioactivity were still measured at 7 days post-dose. About 20% of the drug is excreted in the urine unchanged. Nine metabolites were separated, four of them being characterized.

Pharmacokinetics of 14C-N-N'-dicyclopropyl-methyl-piperazine-dichlorhydrate. 3rd communication: whole-body autoradiographic study in Cynomolgus monkeys after oral administration.

A distribution study was carried out on Cynomolgus monkeys (Macaca fascicularis) dosed orally with 14C-labelled N-N'-dicyclopropyl-methyl-piperazine-dichlor-hydrate 14C-Ino 2628-CZ and sacrificed 2, 8 and 24 h after dosage, using whole-body autoradiography. It is demonstrated that radioactivity is found in all the body; high intakes occur in melanin containing tissues, in blood-forming organs, and in accessory genital glands. Moreover, radioactivity crosses the blood-brain barrier and is mainly localized in hippocampus, caudate, putamen and frontal cortex.