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Biomedical subjects

M Lesne

Publications and source records attributed to M Lesne.

At least 73 records · Page 4Linked to original sources
PubMedDate not supplied

Irreversible binding to proteins after single and repeated daily oral administration of 4-(2,2-diphenylethyl) imidazole (SC-46264) to the Cynomolgus monkey.

SC-46264 is an antagonist of the alpha 2-adrenergic receptor. Distribution and excretion of [14C]-SC-46264 were studied after single and repeated daily oral administrations to the Cynomolgus monkey at a 1.5 mg/kg dose. After a single oral administration, more than 95% of the administered dose was recovered within 48 h in the urine (+/- 60%) and faeces (+/- 40%). Approximately 1.7% remained in the gastro-intestinal (GI) tract and 2% in the animal body. However, the radioactivity remaining in the animal body decreased very slowly from 2 to 1% between 48 and 144 h. An accumulation of very small amounts of radioactivity could be suspected in the plasma, the liver, the thyroid, the adrenals and the kidneys. In a 2 week daily oral administration of [14C]-SC-46264, the amount of total radioactivity remaining in the animal body 24, 48 and 216 h after the last administration was approximately 21, 11 and 5% of the daily administered dose, respectively. It confirmed the accumulation of [14C]-SC-46264 related compound in the plasma, the liver, the thyroid, the adrenals and the kidneys. The minimum plasma concentrations of total radioactivity observed before each administration increased during the treatment and apparently did not yet reach an equilibrium after 14 days. In these plasma samples obtained throughout the study, an increasing fraction of the total radioactivity could not be extracted and was recovered with precipitable material. These observations lead to the hypothesis of an irreversible binding of some material to the proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMedDate not supplied

A further study of the pharmacokinetics of gitoxin in rabbit isolated liver: clearance of 3H-gitoxin.

Hepatic clearance of 3H-gitoxin was studied in the rabbit using an isolated perfused liver technique with an emulsion of a perfluorocarbon. The liposoluble material in the perfusion medium was extracted with dichloromethane, and gitoxin was assayed in the extract by high performance liquid chromatography. Pharmacokinetic parameters were estimated for the liposoluble (dichloromethane soluble) material in the water phase obtained by centrifugation of the emulsion, for the liposoluble material and unchanged gitoxin in the total emulsion. Distribution and elimination half-lives of the liposoluble fraction in the water phase, were estimated to be 0.47 and 4.80 hours respectively, Vd to be 148 ml.g-1 and intrinsic clearance to be 1.16 ml.min-1.g-1; these parameters were compared with those of a previous study with unlabelled gitoxin. Distribution and elimination half-lives of the liposoluble compounds in the emulsion were estimated to be 0.48 and 4.62 hours, Vd to be 47 ml.g-1 and intrinsic clearance to be 1.07 ml.min-1.g-1; these data were compared with those of the liposoluble compounds in the water phase. Distribution and elimination half-lives of unchanged gitoxin in the emulsion were estimated to be 0.22 and 0.70 hour, Vd to be 59 ml.g-1 and intrinsic clearance to be 11.4 ml.min-1.g-1; these data were compared with those of the liposoluble compounds in the emulsion. The subcellular distribution of gitoxin and its metabolites in the liver indicated that 79% of the radioactivity was found in the soluble fraction, no significant binding occurring in the mitochondrial and microsomal fractions.

Animals↗
PubMedDate not supplied

Classification of benzodiazepine receptor agonists, inverse agonists and antagonists using bicuculline in an in vitro test.

The mechanism by which a substance that binds to the benzodiazepine receptor acts as an agonist, an inverse agonist (e.g. methyl-beta-carboline-3-carboxylate (beta-CCM] or an antagonist (e.g. Ro 15-1788) was investigated. For this purpose, we studied the influence of bicuculline, an antagonist of gamma-aminobutyric acid (GABA), on the binding of these substances in crude synaptosomal preparation (P2 fraction) containing high levels of endogenous GABA. Displacement curves were performed, using 3H-flunitrazepam in the absence and in the presence of a high concentration (7.10(-5) M) of bicuculline. The ratios of IC50 values with and without bicuculline were significantly higher than 1 for all benzodiazepine agonists investigated (e.g. 1.91 +/- 0.11 (n = 3) for diazepam), about 1 for Ro 15-1788 (0.94 +/- 0.06 (n = 4)) and lower than 1 for beta-CCE (0.55 +/- 0.05 (n = 4)). Statistically significant differences were also observed among benzodiazepine agonists e.g. between flunitrazepam (a sedative-hypnotic drug) and clonazepam (an anticonvulsant drug) or lorazepam (an anxiolytic drug). These data indicate that the ratios of IC50 values with and without bicuculline might provide the basis for an in vitro, pharmacologically relevant, classification of drugs acting on the benzodiazepine receptor. This procedure does not require extensive washing of the membrane preparation, in contrast to the method in which the ratios of IC50 values were determined with and without addition of GABA.

Animals↗
PubMedDate not supplied

Modulation of ligands binding to the benzodiazepine receptor by an endogenous inhibitor (GABA-modulin) and bicuculline.

We have prepared and purified an endogenous protein (brain neuropeptide) by extraction with 0.025 N acetic acid and precipitation with a saturated ammonium sulfate solution followed by column chromatography. This protein was isolated and partially purified (approx. 500 times). When added to Triton X-100 treated synaptic membrane preparation obtained from rat CNS, this modulates specific high affinity GABA binding site without affecting low affinity site. This protein was called GABA-modulin (GM). GM like bicuculline (competitive GABA antagonist) modulates the affinity of benzodiazepine receptor ligands. But the effect of bicuculline is more important than that of GM. Bicuculline increases or decreases respectively the binding of 3H-beta-CCM or 3H-flunitrazepam by approximately 60%. In the same conditions, at a concentration of 12 micrograms/ml GM increases or decreases respectively the binding of 3H-beta-CCM or 3H-flunitrazepam by approximately 35% and no more modulation was obtained even the concentration of GM was increased. Bicuculline and GM doesn't modify the specific binding of 3H-Ro 15-1788 to the BZD receptor. It is concluded that GM exhibit a lower ability than bicuculline to modulate the binding of the BZD receptor ligands because GM interacts only with the GABA high affinity binding site without affecting the low affinity binding site. These observations suggest that the two GABA binding sites probably interact with the BZD receptor.

Animals↗
PubMedDate not supplied

Interaction of carbolines and some GABA receptor ligands with the GABA and the benzodiazepine receptors.

The binding of different drugs were investigated on benzodiazepines and GABA receptors using P2 fraction or 0.05% Triton X-100 treated membrane preparation (TX-100 P) obtained from rat's CNS. Bicuculline and picrotoxin have the ability to modulate the specific 3H-flunitrazepam binding to its receptor present in P2 fraction; this modulation decreases for bicuculline and disappears for picrotoxin when a TX-100 P was used. Bicuculline at the opposite of picrotoxin displaces 3H-GABA binding on TX-100 P. The beta-CCE binds to the brain benzodiazepines receptor with a high affinity (IC50 = 8.5 nM on TX-100 P) and does not inhibit the binding of 3H-GABA on TX-100 P. On the contrary, other related carbolines such as harmine, harmaline, harmane and harmalol have a much lower ability to inhibit flunitrazepam binding (IC50 between 28 and 130 microM with TX-100 P) and can also inhibit 3H-GABA binding (IC50 between 75 and 186 microM with TX-100 P). But the inhibition of 3H-GABA binding by those related carbolines can't be reversed by a benzodiazepine like flunitrazepam or a benzodiazepine antagonist like Ro 15-1788.

Animals↗
PubMedDate not supplied

Doxorubicin and daunorubicin plasmatic, hepatic and renal disposition in the rabbit with or without enterohepatic circulation.

The pharmacokinetics, metabolism and disposition of doxorubicin and daunorubicin were studied for periods up to 100 hr in rabbits with (group II) or without a biliary fistula (groups I and III) and with (group I) or without (groups II and III) ligatured ureters using high-performance liquid chromatography to separate parent drug and metabolites. The plasma decay of doxorubicin and daunorubicin was triexponential. Metabolites appearing in the plasma after doxorubicin and daunorubicin bolus i.v. injection were respectively doxorubicinol and daunorubicinol, the latter being the major compound after daunorubicin injection. The elimination of daunorubicin was faster than that of doxorubicin. No differences in the elimination were observed between the 3 groups. In bile, 21% of the injected dose of doxorubicin were excreted mainly as the parent drug and 60% of the injected dose of daunorubicin were excreted, mainly as daunorubicinol. Enterohepatic circulation did not affect the biliary excretion of both doxorubicin and daunorubicin. Ligature of ureters increased slightly the biliary excretion of doxorubicin. The hepatic clearance of daunorubicin was greater than that of doxorubicin. The total urinary excretion was not different between the II and III groups and amounted to 11.6 and 12.8% of the injected dose of doxorubicin and daunorubicin, respectively. Metabolic ratios of doxorubicinol/doxorubicin and daunorubicinol/daunorubicin were similar in bile and urine.

Animals↗
PubMedDate not supplied

Pharmacokinetics of daunorubicinol in the rabbit: comparison with daunorubicin.

The pharmacokinetics of daunorubicinol (DOL), the main metabolite of daunorubicin (DNR), was studied in rabbits and compared to that of daunorubicin after an 8 mg/kg dose. High-performance liquid chromatography was used to separate parent drug and metabolites. The plasma disappearance of DNR and DOL was triexponential. DOL was the major species detected in plasma and urine. Both drugs had large volumes of distribution. About 70% of DNR or DOL were bound to plasma proteins and mainly to albumin. Pharmacokinetic parameters of DOL obtained after injection of DOL were different from those calculated for DNR and those calculated for DOL after injection of DNR. The total urinary excretions of DNR or DOL were similar and amounted to 25% of the dose. No conjugates were identified in urine after enzymatic treatment. No fluorescent drug was identified in the feces. Anthracyclines were degraded in vitro in rabbit feces. The rabbit seems to be a good model for the study of anthracycline pharmacokinetics as our results in rabbits after DNR injection were similar to those in human studies.

Animals↗
PubMedDate not supplied

Doxorubicin pharmacokinetics in the rabbit.

The levels of doxorubicin, doxorubicinol and DOX aglycone achieved in plasma, urine and feces after i.v. administration of doxorubicin at 7.9 mg/kg into five New Zealand White rabbits were determined by high-performance liquid chromatography and fluorometry. The parent drug was the major compound found in the plasma. Doxorubicinol and DOX aglycone only appeared in trace amounts in the plasma. The plasma disappearance curves were triphasic with mean half-lives of 2 min, 18 min and 15 h for the alpha-, beta- and gamma-phases, respectively. Plasma protein binding was studied by ultracentrifugation and electrophoresis. Doxorubicin was mainly bound to albumin to an extent of 73.9%. The mean percentage of the administered dose excreted in the urine was 8.0%. Doxorubicinol and doxorubicin were the major compounds present in the urine with small amounts of DOX aglycone. Neither the parent drug nor any fluorescent metabolites were identified in the feces. The rabbit seems to be a good experimental model for the pharmacokinetics study of anthracyclines since the plasma and urine pharmacokinetics parameters and the extent of metabolism are similar in both humans and rabbits.

Animals↗