Biomedical subjects

A E Tufenkji

Publications and source records attributed to A E Tufenkji.

18 recordsLinked to original sources

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

Microdialysis: an alternative for in vitro and in vivo protein binding studies.

The aim of the present study was to compare the performance of conventional equilibrium dialysis method with a microdialysis method in studying drug protein binding. The two methods were assessed by comparing the measured mean unbound drug fraction in different plasma species in vitro in plasma of four different species and at two concentrations of the non-indolic melatonin analog S 20098. For the microdialysis study, the unbound drug fraction was calculated after correction for membrane recovery. Plasma protein binding of S 20098 ranged from 75 to 95%. In humans, rabbits and rats (10 ng/ml), equal unbound percentages were found between equilibrium dialysis and microdialysis. Microdialysis gave slightly but significantly higher values in rat (2000 ng/ml), and in monkey plasma independent of the drug concentration. Microdialysis was also performed in vivo in freely moving rats under steady-state conditions, yielding similar unbound fraction values (26.0 +/- 0.9%) to those obtained using microdialysis probes in rat plasma in vitro (24.4 +/- 1.6%). These results support the use of in vivo microdialysis in pharmacokinetic studies in freely moving animals.

Acetamides↗

PubMed1994

Comparison of the "zero crossing" method in derivative spectroscopy and ultrafiltration for the determination of free and bound fractions of mitoxantrone.

In vitro mitoxantrone binding to human serum, human serum albumin (HSA, 600 microM) and alpha-1-acid glycoprotein (AAG, 15 microM) was investigated by ultrafiltration and the first-derivative spectrophotometry based on the "zero crossing" method. The binding of mitoxantrone to isolated proteins was studied at eight concentrations whose range depended on the protein used. The results showed that mitoxantrone binding to human plasma and HSA involved a saturable binding. The AAG binding involved a saturable binding followed by a non saturable process. Within the concentration range studied, the percent and binding parameters which characterize the drug-protein interaction were comparable in both methods.

Humans↗

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↗

PubMed1993

Pharmacokinetic and pharmacodynamic study of amodiaquine and its two metabolites after a single oral dose in human volunteers.

The pharmacokinetics of amodiaquine (AQ, Flavoquine, CAS 6398-98-7) and its metabolites, mono (AQml) and bis-desethyl amodiaquine (AQm2) were investigated in 8 healthy volunteers after an oral dose of 306.2 mg of AQ. Metabolic clearance was the main AQ elimination pathway. AQ disappeared rapidly, from the plasma and blood, whereas AQml appeared rapidly in keeping with a hepatic first-pass effect. By contrast, AQ was little excreted in urine and AQm2 formation from AQm1 was low. Blood AQm1 concentrations were higher than plasma levels, with an AQm1/AQ concentration ratio of 5 to 10. This result was related to strong uptake of AQm1 by white blood cells, as shown by an in vitro study. On the basis of plasma concentrations, there was no preferential uptake by red blood cells, the pharmacological target cells; effective AQ concentrations should thus be analyzed in plasma rather than in whole blood. The inhibitory activity of patients' sera on Plasmodium falciparum growth in vitro appears to be directly related to the AQm1 concentration.

Adult↗

PubMed1993

[Monoxycarbogenic reaction of chloral: application to the obtention of carboxyhemoglobin and to its determination in blood].

Carbon monoxide CO, generated from chloral (10(-2) M) in a dilution of hemochrome (pH 13), turns the solution of hemochrome into a solution of carboxyhemoglobin. The spectrum of this solution is identical to the one obtained after bubbling with CO. The reaction is fast and makes it possible to determine the percentage of carboxyhemoglobinemia in whole blood.

Carbon Monoxide↗

PubMed1993

Pharmacokinetic study of fentiazac and its main metabolite hydroxyfentiazac in the elderly.

The pharmacokinetics of fentiazac (F, CAS 18046-21-4) and hydroxyfentiazac (OH-F) were estimated in 12 elderly (> 76 years). After an oral single dose of 200 mg F, the plasma and urine profiles were determined using high-performance liquid chromatography with a fluorescence detection. When compared to results obtained in young adults, the maximum plasma concentrations (5.4 +/- 1.9 mg/l) and-the time to reach them were identical. The terminal half-life (7.0 +/- 9.1 h) was longer, due to a slight increase of the apparent volume of distribution and a decrease of the elimination clearance. The findings suggest that the dosage regimen of this drug should be decreased in the elderly. Moreover, the variability of the pharmacokinetics being larger, individual adaptation of the daily dose should be performed.

Acetates↗

PubMed1993

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.

Administration, Oral↗

PubMed1993

Pharmacokinetics of 14C-N-N'-dicyclopropyl-methyl-piperazine-dichlorhydrate. 2nd communication: tissue distribution in rats.

The distribution of radioactivity in rats after intravenous or oral administration of 14C-labelled N-N'-dicyclopropyl-methyl-piperazine-dichlorhydrate (14C-Ino 2628-CZ) demonstrated that the labelled compound was widely distributed in the body. An important diffusion of the isotope was found in the central nervous system, the gastric mucosa and several glands. Only small amounts of radioactivity were found in these organs 24 h after dosage.

Animals↗

PubMed1992

First-derivative spectroscopic determination of binding characteristics of rifampicin to human albumin and serum.

A first-derivative spectroscopic method for the simultaneous determination of bound and unbound drug in human serum and serum albumin solution was developed. As an example, the binding characteristics of rifampicin were studied. In serum albumin solution, the rifampicin bound and unbound fractions were determined at 473.5 and 475.8 nm, respectively. For human serum, the unbound fraction was determined at 479.4 nm. The results obtained by the first-derivative spectroscopic method were in agreement with those obtained by equilibrium dialysis. The proposed method is very simple and accurate when applied to measurements of drug:protein binding. Moreover, it allows a direct measurement of the bound and unbound forms without any physical separation.

Humans↗

PubMed1992

Clinical pharmacokinetics of alpha 1-antitrypsin in homozygous PiZ deficient patients.

A pharmacokinetic study of alpha 1-antitrypsin (ATT) was performed in 2 groups of homozygous PiZ-deficient patients (treated and untreated) and 1 group of healthy volunteers. The distribution of the 131I-labelled protein corresponds to a 3-compartment model. The intravenously administered protein diffused quickly to the extravascular compartment where some retention occurred. No significant difference in AAT metabolism was observed between the 3 groups. The half-life of the injected protein is slightly longer than 2.5 days. The AAT protein was not stored. These results confirm the observations collected during the clinical trials. That is, a weekly infusion is necessary to obtain stable serum AAT concentrations. Monthly infusions are unable to maintain a 'plateau' phase. The periodicity may be limited to every 2 weeks.

Adult↗

PubMed1991

Pharmacokinetics of ampicillin and pentobarbital in the course of subclinical fascioliasis in sheep.

Pharmacokinetics of two common veterinary drugs, ampicillin and pentobarbital, were determined in sheep before and four, eight, 12, 17 and 21 weeks after infestation of animals by an oral administration of 150 metacercariae of Fasciola hepatica. The parasite infestation was ascertained by clinical observation of the animals. The pharmacokinetics of ampicillin were not significantly affected by the liver parasitism but the disposition of pentobarbital changed. A significant increase in elimination half-life (around 180 per cent), volume of distribution (130 per cent) and mean residence time (154 to 170 per cent) was observed in sheep infected by the parasite for four to 12 weeks. In these animals, duration of narcosis caused by pentobarbital was prolonged 1.8-fold. The results suggested that both reduced elimination of pentobarbital and impaired distribution of the drug would be responsible for the prolonged duration of narcosis in infected animals.

Ampicillin↗

PubMed1991

Decrease in albendazole sulphonation during experimental fascioliasis in sheep.

1. The in vivo S-oxidation of albendazole was measured from the pharmacokinetic profile of albendazole sulphoxide and sulphone determined in young male sheep receiving oral albendazole (1.9 mg/kg). Studies were carried out before, and each month after, oral infestation by 150 metacercariae of Fasciola hepatica. 2. Parasitic pathology was ascertained by clinical observation of animals, and the increase in plasma antibodies directed against liver flukes. 3. Rate of conversion of sulphoxide to sulphone and rate of sulphone elimination, were respectively decreased by 47% and 87% at week 8 post-infection, whereas significant increases in the area under plasma sulphone concentrations versus time curve and mean residence time, occurred 4-12 weeks following the infestation. 4. A 58% decrease in albendazole sulphonation was demonstrated in liver microsomal preparations obtained from 8-week-infected sheep, while there was no change in the FAD-directed sulphoxidation of albendazole. 5. The transient impairment of albendazole sulphonation could be related to the decrease in liver microsomal cytochrome P450-dependent monooxygenases observed in sheep with a similar parasitic pathology.

Administration, Oral↗

PubMed1991

Protein binding of methotrexate to human albumin and serum. A first derivative spectroscopic analysis.

Usual methods allowing the measurement of the free concentration of a drug in serum, i.e. equilibrium dialysis, ultrafiltration and ultracentrifugation, are generally based on a physical separation of the bound and free fractions. During this, variations or errors may occur which are probably at the origin of the variability of the previously published results for methotrexate (CAS 59-05-2). In order to verify these results as well as to experience a technique recently applied to rifampicine the first derivative spectroscopic analysis was used to estimate the bound and free fractions of methotrexate in human serum and serum albumin (HSA). Free drug concentrations were measured at 377 nm and the bound form at 372.5 nm. In human serum, bound methotrexate was 54.1% on average for total concentrations ranging from 10(-5) mol/l to 10(-3) mol/l, without any saturation. With HSA, a saturation occurred. Scatchard analysis showed one family of binding sites characterized by 2 binding sites and an affinity constant of 3200 mol/l, in mean, values close to that previously calculated using equilibrium dialysis.

Binding Sites↗

PubMed1989

Comparative incidence of experimental fascioliasis on corticosteroid pharmacokinetics in sheep.

1. The kinetics of intravenously administered prednisone (0.5 mg/kg) and methylprednisolone hemisuccinate (4 mg/kg) were compared in two groups of four young male sheep before and regularly after experimental infestation with 150 metacercariae of Fasciola hepatica and 5 or 7 weeks following a flukicidal treatment administered post-infection at week 25. 2. Parasitic pathology was ascertained by clinical observation and by the increase in plasma antibodies directed against liver flukes. 3. The disposition of prednisone was altered with a significant decrease of plasma clearance occurring from eleven weeks after infection onwards. This change was parallel to an increase in the mean residence time of prednisone and of its major metabolite (prednisolone). 4. The same parasitic burden provoked only a slight decrease in the elimination half-life of methylprednisolone alcohol when its hemisuccinate ester was administered.

Animals↗

PubMed1988

Incidence of a subclinical fascioliasis on antipyrine clearance and metabolite excretion in sheep.

1. The pharmacokinetics of i.v. antipyrine (25 mg/kg) used as a model compound, were determined in young male sheep, before and each month after an oral infestation by 150 metacercariae of Fasciola hepatica, and 8 weeks following a flukicidal treatment. 2. The parasitic pathology was ascertained by the clinical observation of animals and the increase in plasma antibodies directed against liver flukes. 3. A significant decrease in the total plasma clearance of the drug occurred by week 4 to 16, and a 1.7 fold increase in mean residence time occurred by week 12 post-infection. 4. Urinary excretion of antipyrine metabolites was determined before and 8 weeks following the infestation. 4-Hydroxyantipyrine was the major urinary metabolite and its excretion was decreased by 30% in infected sheep, whereas there was no change in the excretion of norantipyrine, 3-hydroxymethylantipyrine or unmetabolized drug. 5. It is concluded that the impairment of antipyrine clearance in the course of fascioliasis could be related to the decrease in liver microsomal cytochrome P-450-dependent mono-oxygenases observed in sheep with a similar parasitic burden.

Animals↗

PubMed1987

Pharmacokinetics of sulphobromophthalein, lidocaine and indocyanine green in the course of subclinical fascioliasis in sheep.

The pharmacokinetics of three drugs proposed for the assessment of liver function: sulphobromophthalein (BSP), lidocaine and indocyanine green (ICG) were determined in sheep four, eight, 12, 16 and 24 weeks after their infestation by an oral administration of 150 metacercariae of Fasciola hepatica. The disposition of BSP was altered by a significant decrease in its total plasma clearance from eight weeks after infection onwards. This change could be related to the low values of the elimination rate constant consistent with a reduced liver cytosolic conjugation of the dye to glutathione. Lidocaine pharmacokinetics were unaffected by parasitism and the only effect on ICG was an increased volume of distribution consistent with the liver hypertrophy caused by the subclinical fascioliasis.

Animals↗

PubMedDate not supplied

Incidence of experimental fascioliasis on the activity of drug-metabolizing enzymes in lamb liver.

The purpose of this investigation was to determine the effects of a subclinical fascioliasis at various stages of its development (by week--4, 8, 12, and 16 weeks after the infestation by an oral administration of 150 metacercariae of Fasciola hepatica) on the activity of some hepatic drug-metabolizing systems in lamb. The parasitic pathology was ascertained at autopsy and by clinical observation of animals. Hepatic microsomal cytochrome P-450 content was significantly decreased (by 9-22%) in all infected groups of animals. In early stages of the parasitic disease, decreases in cytochrome b5 content (10-18%) and ethoxycoumarin O-deethylase (25%) were observed, whereas aminopyrine N-demethylase, benzphetamine N-demethylase, and aniline hydroxylase were significantly lowered by 8 to 16 weeks postinfection. Among investigated transferases, glutathione transferase was only decreased (28%) in animals killed 16 weeks after the infestation; in these animals a significant increase in microsomal gamma-glutamyltransferase was observed, probably related to the elevated plasma activity of this enzyme. By 8 weeks postinfection, a simultaneous increase in cytosolic calcium (38%) and decrease in cytosolic glutathione (22%) would correspond to an oxidative cell injury occurring in the course of fascioliasis. The consequences of the fascioliasis-induced decreases in liver-oxidative and conjugative liver drug metabolism are discussed.

7-Alkoxycoumarin O-Dealkylase↗