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Biomedical subjects

P Galtier

Publications and source records attributed to P Galtier.

At least 55 records · Page 3Linked to original sources
PubMed1996

Pharmacological basis for hepatic drug metabolism in sheep.

Age-related changes in hepatic drug metabolizing activities of Lacaune ewes were determined in foetal, neonatal, growing, pregnant and adult animals. The ontogenic evolution of cytochrome P450 was compared to those of microsomal monooxygenases and some microsomal and cytosolic transferases. The involvement of two purified izoenzymes P4502B and P4503A was determined in the N-demethylation of various substrates and the hydroxylations of progesterone. An experimental fascioliasis, provoked by the oral administration of 150 metacercariae of Fasciola hepatica to sheep, was proposed as a pathological model. Its effect was measured on the pharmacokinetics of various hepatic tracers and veterinary drugs. The mean residence times of antipyrine, pentobarbital, albendazole and mebendazole were increased in infected lambs with consequences on the urinary excretion of 4-hydroxyantipyrine, prolongation of pentobarbital-induced sleeping time, elimination of albendazole sulfone and reduced mebendazole. The characteristic decrease in liver cytochrome P450 could be responsible for most of the pharmacokinetic and pharmacodynamic changes observed in fluke-infected ruminants.

Aging↗
PubMed1996

Plasma profile study of moxidectin in a cow and its suckling calf.

The plasma concentration of moxidectin, a macrocyclic lactone endectocide, was investigated in a cow and its suckling calf, using a new chemical assay, following subcutaneous injection (0.2 mg/kg) in the cow. The most striking result was the persistence of moxidectin in the plasma of the cow (mean residence time: 25.66 days). Moxidectin was also detected in the plasma of the calf as a result of the excretion of the drug in the cow's milk and its ingestion by the calf. The cow and calf plasma concentrations and pharmacokinetic parameters showed parallel disposition of the drug. The suckling calf received about 5% of the dose from the cow via the milk.

Animals↗
PubMed1996

[Study of plasma and hepatic hydrolysis of nitroxinil derivatives].

Seven esters derivatives of Nitroxinil were prepared and their structures were assigned by IR and 1H-NMR spectroscopy. The rate of plasma and hepatic hydrolysis were evaluated in vitro in sheep and rabbit. In view of this profile of activity, pivaloyl derivative merits evaluation, in vivo.

Animals↗
PubMed1996

Ontogenic development of drug-metabolizing enzymes in male chicken liver.

The ontogenic study of the hepatic biotransformation enzymes revealed the early development of both oxidative and conjugative enzymes in male chickens ranging in age from 3 to 12 weeks. Although the rate of microsomal cytochrome P450 reactions progressively increased during the first 9 weeks, it decreased thereafter. Furthermore, the proteins revealed by the antibodies to anti-cytochrome P450 1A2, 2B4, 2C7, and 3A4 appeared to be constitutively expressed. Hepatic monooxygenases were characterized by different developmental patterns. The demethylase activities increased progressively up to 9 weeks, then they declined, in 12 weeks reaching the activity level observed in 3-week-old chickens. In contrast, alkoxyresorufin O-dealkylases and benzopyrene hydroxylase activities continued to increase with age. Significant variability was noted for aniline hydroxylase. Among conjugation enzymes, UDP-glucuronyltransferase towards p-nitrophenol and isoniazid N-acetyltransferase activities increased with the age of the fowl, but with different profiles. Concerning glutathione S-transferase accepting 1-chloro-2,4-dinitrobenzene or 1,2-dichloro-4-nitrobenzene, the chickens aged from 3 to 9 weeks were less well developed in this enzyme than 12-week-old ones.

Age Factors↗
PubMed1995

Determination of moxidectin in plasma by high-performance liquid chromatography with automated solid-phase extraction and fluorescence detection.

Moxidectin is a newly developed potent anthelmintic agent with a high potency although present at very low concentration in cattle plasma. A method is described for the determination of moxidectin in plasma using high-performance liquid chromatography with fluorescence detection (excitation and emission wavelengths 383 and 447 nm, respectively). The fluorescent derivative was obtained by a dehydrative reaction with trifluoroacetic anhydride and N-methylimidazole. The method employs 1-ml plasma samples and has linear calibration graphs (r = 0.997) over the concentration range studied, i.e., 0.1-10 ng/ml. Solid-phase extraction using the Benchmate procedure was used for sample preparation. Recoveries at low concentrations (0.1-10 ng/ml) were higher than 75%. The limit of quantification was 0.1 ng/ml (C.V. 6.95%). The method is suitable for the pharmacokinetic study of moxidectin after subcutaneous administration to cows.

Animals↗
PubMed1995

Evidence for the ligand-independent activation of the AH receptor.

Benzimidazole derivatives are potent inducers of CYP1A1 in rabbit and human hepatocytes, but apparently do not bind the AH receptor. To resolve this paradoxical behaviour, studies have been concerned with the question of whether an alternative ligand-independent mechanism could explain the activation of the AH receptor. From experiments in cultured rabbit hepatocytes we show that benzimidazoles bind early and transiently to an unknown protein. Moreover, they are able to deplete the AHR in a time- and dose-dependent manner. In contrast, benzimidazoles are unable to induce CYP1A1 mRNA in mouse hepa-1 cells and to deplete the high-affinity AHR form from these cells. Taken together these data suggest that a signal transduction pathway, similar to that involved in the ligand-independent activation of steroid receptors, could only activate the low-affinity forms of AHR as those existing in rabbit and human cells.

Animals↗
PubMed1995

Comparison of hepatic and extrahepatic drug-metabolizing enzyme activities in rats given single or multiple challenge infections with Fasciola hepatica.

The activity of drug-metabolizing enzymes was compared in liver, kidneys and lungs of rats given single or repetitive fluke infections. Fascioliasis was induced by oral administration of 20 metacercariae of F. hepatica to rats, either 6, or 12 and 6, or 12, 9 and 6 weeks before sacrifice. In the liver of mono-infected rats, significant reductions (24-67%) were observed in microsomal content of cytochrome P450 and all P450-dependent monooxygenases investigated. Conjugations to glutathione or acetate were lowered by 34-50% in these animals. In multiply infected animals, a majority of specific enzymatic activities were unchanged, while some monooxygenase activities such as aminopyrine demethylation or benzo(a)pyrene hydroxylation were increased by 26-76% in the liver of tri-infected rats. A renal compensatory process occurred in all infected groups, since cytochrome P450, benzphetamine demethylation and glutathione conjugation were significantly increased. By contrast, dealkylation of benzphetamine and pentoxyresorufin were decreased in the lungs of monoinfected rats. The development of parasite resistance would account for the recovery of liver drug metabolizing capabilities in multi-infected animals.

Animals↗
PubMed1994

Thiabendazole is an inducer of cytochrome P4501A1 in cultured rabbit hepatocytes.

The effect of TBZ (30-100 microM) was investigated on cytochromes P450 of cultured rabbit hepatocytes considered 72 h after plating. At the highest concentrations and without apparent cellular toxicity, the drug provokes a dose-dependent increase in total microsomal cytochrome P450 and a rise in EROD activity which was correlated to a specific increase in P4501A1 level. Northern blot analysis of RNA reveals an increased level of mRNA specific to P4501A1. The transcriptional activation of this isoenzyme is proposed because of the significant inhibition of the above-mentioned increases when actinomycin was added to the culture medium. Data obtained from competition experiments demonstrate that TBZ is not a ligand of Ah receptor. A down-regulation process could explain the slight decrease in both ANOH and P4502E1 level observed in hepatocytes treated with the highest dose of TBZ.

Animals↗
PubMed1994

The pig as a model for studying AH receptor and other PAH-binding proteins in man.

In this report we compare the three major binding proteins existing in hepatic cytosols of pig and human. Many data suggest that for the AH receptor, which mediates the biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a structural as well as a functional variability exists across species. Similar conclusions can be drawn from the interspecies characterization of benzo(a)pyrene binding proteins, namely the 4S protein and the 8S protein. Using fractionation procedures such as sucrose gradient sedimentation and gel permeation chromatography we obtained enriched fractions containing each of these binding proteins. By saturation experiments and analysis of data by Scatchard and Woolf plots we determined binding characteristics and we conclude that pig and human AH receptors were closely related proteins since their Kd (18 +/- 0.4nM) were found quite similar. On the other hand, 4S proteins from pig (Kd = 16.7 nM; Bmax = 5.5 pmol/mg) and from human (Kd = 14 nM; Bmax = 4.5 pmol/mg) as well as 8S proteins (Kd approximately 300 nM) also exhibit remarkable similarities.

Animals↗
PubMed1994

Assessment of hepatic insufficiency model in the rabbit using carbon tetrachloride intoxication.

The objective of the present study was to compare two doses (0.035 and 0.1 mL/kg) of carbon tetrachloride given intragastrically or intraperitoneally to rabbits during 8 weeks to induce a model of liver insufficiency. All animals developed pericentrolobular fibrosis. The intensity of the fibrosis was proportional to the dose. An increase in the plasma enzymatic activities (ALAT, ASAT, gamma GT) was related to the dose. Plasma proteins and creatinine levels remained unaltered during the experiment. Hepatic microsomal cytochrome P450 was reduced in treated animals in relation to the dose, as was glutathione-S-transferase enzymatic activity, whereas no change was observed in UDP glucuronyltransferase activity. When antipyrine was administered to the intragastric group, a reduction of total body clearances and an increase in half-lives and areas under the curve were observed in relation to a reduction of oxidation capacities. After intraperitoneal intoxication, only the total body clearance with a 0.1 mL/kg dose increased significantly. With the exception of the intragastric dose of 0.035 mL/kg, the pharmacokinetics of indocyanine green showed a decrease in total body clearances and an increase in areas under the curve. Distribution volumes decreased in treated animals whereas half-lives remained constant. After an intragastric dose of 0.035 mL/kg, only an increase in half-life and a decrease in total body clearance were observed. All these results indicate that rabbits chronically intoxicated with CCl4 may be an adequate model for studying the influence of hepatic insufficiency on pharmacokinetic disposition.

Alanine Transaminase↗
PubMed1994

Fasciola hepatica: liver microsomal membrane functions in host rat.

Changes in different microsomal membrane functions were measured in the liver of rats 3, 6, or 9 weeks following an oral infection with 20 metacercariae of Fasciola hepatica. The parasitic pathology noted at autopsy was accompanied by increased levels in both plasma aspartate aminotransferase (EC 2.6.1.1) and microsomal gamma-glutamyltransferase (EC 2.3.2.2). Heme oxygenase activity of microsomes was significantly decreased by Weeks 3 and 6 postinfection and this decrease correlates with those of total microsomal cytochrome P450 and certain P450-dependent monooxygenase activities, namely, benzphetamine demethylation, ethoxycoumarin deethylation, and benzopyrene hydroxylation. Microsomal epoxide hydrolase (EC 3.3.2.3) was only altered 6 weeks after the infection. During the early stages of the parasitism, there were decreases in both microsomal calcium uptake and calcium ATPphosphohydrolase activity (EC 2.6.1.1), whereas membrane fluidity, estimated by the order parameter S, was lower in the infected rats than that in the controls. These alterations could be related to the already described increase in liver cytosolic calcium or lipid peroxidation which occurs in experimental fascioliasis.

Animals↗
PubMed1994

Fasciola hepatica: mebendazole and thiabendazole pharmacokinetics in sheep.

Pharmacokinetics of the two anthelmintic drugs mebendazole and thiabendazole were determined in sheep before and 4, 8, 13, 19, and 25 weeks after an infestation of animals by an oral administration of 150 metacercariae of Fasciola hepatica. The parasitic pathology was ascertained by the increase in plasma enzyme activities of glutamate dehydrogenase and gamma-glutamyltransferase. After oral administration of mebendazole (25 mg.kg-1), the parent drug and especially its reduced metabolite were present in plasma of animals. A significant 1.5- to 2.7-fold increase in the mean residence time occurred by Weeks 13 to 25 postinfection. This change was related to decreases in both the elimination from the pharmacokinetic compartment representing the reduced metabolite and the area under the curve of plasma metabolite concentration versus time. A 59% decrease in MBZ reduction was demonstrated in liver microsomes prepared from 12-week-infected sheep. This reductase activity was characterized by NADPH dependency and a pH peak activity of 6.0 and was competitively inhibited by daunomycin. In sheep receiving a 50 mg.kg-1 oral dose of thiabendazole, fascioliasis provoked only decreased plasma concentrations of the metabolite 5-hydroxythiabendazole by Weeks 4 to 25 postinfection. This change parallels an increase in urinary excretion of free metabolite but this is of minor significance in the general fate of the drug because of the prevalence of excretion as conjugates. In summary, fascioliasis appears to have more of an effect on the pharmacokinetics of mebendazole, a drug intensively metabolized by the liver into a metabolite present at high concentrations in the plasma of animals and humans.

Administration, Oral↗
PubMed1994

Consequences of challenge infections with Fasciola hepatica on rat liver P450-dependent metabolism of sex hormones.

The effect of single or repetitive fluke-infections on rat liver steroid hormone metabolism was studied. Fascioliasis was induced by oral administration of 20 metacercariae of Fasciola hepatica to rats, by week-6 (mono-infected) or 12 and 6 (bi-infected), or 12, 9 and 6 (tri-infected) before killing. Total microsomal cytochrome P450 and P450 isoenzymes were measured spectrophotometrically and by Western-blot analysis, respectively. Progesterone and testosterone metabolism were quantified by normal phase high performance liquid chromatography. In control rats, progesterone and testosterone were mainly converted to 2 alpha- and 16 alpha-hydroxymetabolites. In the liver of mono-infected rats, hepatic cytochrome P450 was significantly decreased by 36-64% whereas the expression of all investigated isoenzymes was decreased by 36-82% with the exception of the unchanged P4502E1. 16 alpha- and 2 alpha-hydroxylations of progesterone and testosterone were significantly decreased by 50-90%, these decreases were correlated with those of P4502B1/2 and P4502C11 isoenzymes, respectively. In bi- and tri-infected rats, steroid hormones were metabolized similarly to control rats. The return of steroid drug metabolizing enzyme activities to control level could be related to the immune response associated to the development of the animal resistance to the parasitic infection.

Animals↗
PubMed1993

Determination of aditoprim and its oxidative metabolites in plasma and microsomal incubation mixtures by high-performance liquid chromatography.

A high-performance liquid chromatographic method is presented for the determination of aditoprim (ADP) and its two oxidative metabolites in biological fluids including sheep plasma and the incubation medium of liver microsomes. The compounds were separated using a highly deactivated C18 column; the mobile phase consisted of an 0.05 M phosphate buffer (pH 6) and acetonitrile in a ratio of 90:10 (v/v). The eluate was quantified by ultraviolet detection at 230 nm. Calibration curves were linear from 0.25 to 5 micrograms/ml. The limit of detection was 0.05 microgram/ml. In an in vivo kinetic study in sheep, N-monodesmethyl-ADP and N-didesmethyl-ADP appeared to be equally important metabolites. In contrast, in in vitro metabolism studies using liver microsomes from different animal species including sheep, N-didesmethyl-ADP was formed predominantly.

Animals↗
PubMed1993

Disposition of prednisolone in the course of subclinical fascioliasis in sheep.

1. The in vivo disposition of prednisolone in sheep was studied before, during and after recovery from experimental hepatitis of parasitical origin (fascioliasis). 2. After i.v. administration, plasma clearance of prednisolone was increased from 0.93 +/- 0.13 l/kg per h before infection to 1.73 +/- 0.50 l/kg per h at week 21 post-infection. The steady state volume of distribution was increased from 0.45 +/- 0.08 l/kg during the control period to 1.26 +/- 0.44 l/kg at week 5 post-infection. 3. None of the prednisolone binding parameters (specific and non-specific sites) was modified, and the overall mean unbound fraction was 24%. 4. Urinary excretion of unchanged prednisolone was low and only a trace of 6 beta-hydroxy-prednisolone was identified.

Animals↗
PubMed1993

Ivermectin in goat plasma and milk after subcutaneous injection.

The pharmacokinetics and mammary excretion of ivermectin were determined in goats following a single sc administration (0.2 mg/kg). Kinetic analysis of plasma and milk levels was performed using a 1-compartment model. The maximum plasma concentration of 6.12 ng/ml occurred at 2.85 d; the half-life of 4.03 d was similar to the value in sheep (3.68 d). Ivermectin was detected in the milk at the first sampling time and thereafter for at least 25 d. Comparison of the milk and plasma data shows the parallel disposition of the drug in milk and plasma with a milk-plasma concentration ratio of 1.08 +/- 0.23. In conclusion, the persistence of the drug in plasma is reflected in the duration of the presence of ivermectin in milk.

Absorption↗
PubMed1993

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.

Administration, Oral↗