PubMed Health⌕ Search

Biomedical subjects

J P Thénot

Publications and source records attributed to J P Thénot.

At least 19 recordsLinked to original sources
PubMed2004

New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humans.

Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax=1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax=0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1.

Administration, Oral↗
PubMed2001

Population pharmacokinetic analysis and optimization of the experimental design for mizolastine solution in children.

Mizolastine is a second generation antihistamine agent approved in Europe for the treatment of allergic rhinitis and skin conditions for which Sanofi-Synthélabo is developing a pediatric solution. Our objective was to design the population pharmacokinetic (PK) study of mizolastine pediatric solution in children. A bioavailability study of this solution compared to the marketed tablet was performed in 18 young volunteers. These PK data were analyzed by nonlinear regression using a two-compartment open model with zero-order absorption. From the estimated parameters, we designed population PK studies in two groups of children: 6 to 12 years and 2 to 6 years, respectively. To compare several population designs and to derive the optimal ones, we used the determinant of the Fisher information matrix of the population characteristics using a first-order expansion of the model. We have evaluated a "reference" population design with 10 samples (from 0.25 to 36 hr after drug intake) per child in 6 children, which could not be implemented in practice for ethical reasons. We then derived optimal population designs with 1, 2, 3, 4, or 5 samples per child and a total of 60 samples. Finally, the designs that were implemented in the population PK study were "compromise" population designs with 60 samples; one defined for 20 children 6 to 12 years old, and one with 24 children 2 to 6 years. In the older group, the population design involved 8 children with a catheter from which 6 samples at time 0.25, 0.5, 0.75, 2, 3, and 6 hr after drug intake are collected, and 12 children with only one sample at time 8, 12, 24, or 36 hr. In the younger group, the population design involved 15 children with a catheter who are divided in three groups with four samples at different times from 0.25 to 6 hr after drug intake, and 12 children with only one sample at time 8, 12, 18, or 24 hr. The expected average increase of variances of these designs compared to the reference design were 1.6 and 1.8 for the older and younger group, respectively, which was decided to be acceptable. Better population designs would have involved three groups of children with five samples per child but could not be implemented in practice. The data of the PK study in children 6 to 12 years were available and were analyzed using NONMEM. A total of 53 concentrations were obtained in 18 children. The same two-compartment model with zero-order absorption was used. The interindividual variability in children was small. The estimated population parameters in children 6 to 12 years, were 0.28 L/kg for Vc/F, 0.10 L/hr per kg for CL/F, 0.53 hr-1 for lambda 1, 0.076 hr-1 for lambda 2, and 0.49 hr for Tabs. These values were close to the median values observed in young volunteers when standardized to 70 kg; notably, CL/F in L/hr per kg was similar, so that a dose of 0.15 mg/kg o.d. for mizolastine pediatric solution should give an equivalent area under the curve to a 10 mg o.d. tablet in adults.

Adult↗
PubMed1998

Population pharmacokinetic analysis of mizolastine and validation from sparse data on patients using the nonparametric maximum likelihood method.

A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.

Benzimidazoles↗
PubMed1995

A noncompetitive enzyme immunoassay for rat prolactin.

A sensitive and specific noncompetitive rat prolactin (rPRL) enzyme immunoassay (EIA) is described. In this assay, the same rabbit anti-rPRL antibody is both adsorbed to a solid-phase support, i.e. 96-well microtiter plates and conjugated covalently to peroxidase as a tracer. PRL being sandwiched between antibody molecules, the enzymatic activity is thus proportional to the amount of rPRL concentration. This assay was found highly specific for rat PRL and displayed a sensitivity of 12.5 pg/well (0.125 ng/ml) of NIH-RP2 equivalents. The intra-assay and inter-assay coefficients of variation were less than 10% over a wide range of rPRL concentration (0.25-40 ng/ml). This rPRL-EIA permits to quantify PRL in culture media or biological samples containing up to 25% of plasma. Comparison with a radioimmunoassay revealed a good correlation (r = 0.984, the slope = 1.04). This EIA is rapid, results being obtained within 4h30 or 18h30 depending on the nature of the biological samples. The tracer, easily performed with a low cost enzyme, can be stored for very long durations. Thus, this sensitive and rapid assay provides a valuable method for measuring rPRL.

Animals↗
PubMed1995

Pharmacokinetic and bioavailability of diltiazem sustained-release: influence of food and time of administration.

Diltiazem is a calcium channel blocking agent known to be effective in the treatment of angina pectoris, hypertension and supraventricular arrhythmias. To improve the conditions of diltiazem administration in the treatment of hypertensive patients, a sustained-release formulation (Mono-Tildiem LP 300 mg) allowing a single daily oral administration has been developed. The aim of the present study was to first evaluate the influence of food intake and second to evaluate those of the time of administration on the pharmacokinetic parameters and the bioavailability of this sustained-release formulation. The influence of these factors was investigated over two different open, randomized, cross-over studies in 12 healthy volunteers. Although a significant decrease in Tmax and an increase in Cmax occurred when diltiazem sustained-release was administered with food intake, AUC0-48, and therefore the fraction absorbed, were not modified either by concurrent food intake or by different times of administration. The minor modifications of pharmacokinetic parameters of diltiazem sustained release observed were unlikely to induce any clinical consequence.

Administration, Oral↗
PubMed1995

Oxidative metabolism of zolpidem by human liver cytochrome P450S.

The aim of this study was to identify the form(s) of cytochrome P450 (CYP) responsible for the biotransformation of zolpidem to its alcohol derivatives which, after rapid conversion to carboxylic acids, represents the main way of metabolism in humans. In human liver microsomes, zolpidem was converted to alcohol derivatives. Production of these correlated with the level of CYP3A4 and with cyclosporin oxidation and erythromycin N-demethylation activities, but not with the level of CYP1A2 nor with ethoxyresorufin O-deethylation or S-mephenytoin 4'-hydroxylation activities. Liver microsomes from CYP2D6-deficient patients exhibited normal activity. Production of alcohol derivatives was significantly inhibited by anti-CYP3A antibodies and by ketoconazole. Antibodies directed against other CYP forms (including CYP1A1, CYP1A2, CYP2A6, CYP2B4, and CYP2C8), and CYP-specific substrates or inhibitors (including propranolol, coumarin, mephenytoin, sulfaphenazole, quinidine, aniline, and lauric acid) produced a moderate or no inhibitory effect. cDNA-expressed CYP3A4 and CYP1A2 generated significant amounts of one of the alcohol derivatives, whereas CYP2D6 generated both of them in similar amounts. In human hepatocytes in primary culture, zolpidem was extensively and almost exclusively converted to one of the carboxylic acid derivatives, the main species identified in vivo. Treatment of cells with inducers of CYP1A (beta-naphthoflavone) and CYP3A (rifampicin and phenobarbital) greatly increased the rate of production of this metabolite. We conclude that the formation of alcohol derivatives of zolpidem is rate-limiting and principally mediated by CYP3A4. Both CYP1A2 and CYP2D6 participate in alcohol formation; but, because of their low relative level of expression in the human liver, their contribution is minor.

Adult↗
PubMed1992

Determination of zolpidem, a new sleep-inducing agent, and its metabolites in biological fluids: pharmacokinetics, drug metabolism and overdosing investigations in humans.

For the determination of zolpidem, a new sleep inducer, and its metabolites in human plasma and urine, three methods were developed that are suitable for pharmacokinetics, drug metabolism and overdosing investigations. The methods used for pharmacokinetic and drug metabolism studies are based on column-switching high-performance liquid chromatography; they do not require any sample manipulation because the plasma or diluted urine is injected into a pre-column where clean-up and preconcentration take place. The analytes are transferred by valve-switching to the C18 analytical column for chromatography. To investigate overdose cases, urine samples only are used: the method is simple, because the diluted urine can be injected directly into the analytical column (phenyl type). This allows the identification and quantification of the principal urinary metabolite of zolpidem, the unchanged drug being practically undetectable. All the methods use fluorescence detection, which affords high sensitivity and selectivity. It is necessary to use a method capable of the determination of metabolites even if these are apparently pharmacologically inactive, because in different physiopathological populations the qualitative and quantitative metabolic profiles of zolpidem could be different. The method designed for the investigation of (accidental or deliberate) overdose cases is, as required on such occasions, simple and rapid, with good selectivity with respect to commonly prescribed psychotropic drugs.

Chromatography, High Pressure Liquid↗
PubMed1991

Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses.

In a double-blind, placebo-controlled, cross-over experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0-54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1-4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng.ml-1, respectively. In 50% of the subjects Cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng.ml-1.h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18.1, and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Pharmacokinetics of antihypertensive drugs in the neonatal period.

A consistent body of evidence indicates that in the preterm and full-term newborn drug disposition is reduced when compared to that of infants, grown-up children, and adults. Newborns are rarely treated directly with antihypertensive agents; however they can be exposed to the action of various antihypertensive drugs in utero and during their first week of extrauterine life in the case of hypertensive mothers treated through pregnancy. In such cases, the persistence of the antihypertensive agent during the first days of life may have important consequences on neonatal haemodynamics and on the function and the maturation of vital organs such as lungs and kidneys. The available information on the placental transfer and neonatal pharmacokinetics of alpha-methyldopa, clonidine, acebutolol, atenolol, betaxolol, metoprolol, propanolol, oxprenolol, and latetalol, are reviewed. Each product has its own pharmacokinetic characteristics which should influence, depending on the clinical situation, the therapeutic choice. In the presence of comparable efficacy, preference should be given to compounds with high bioavailability, eliminated mainly via metabolic degradation, with no active metabolites. In all cases, treatment should be discontinued 8-12 h before delivery.

Antihypertensive Agents↗
PubMed1989

Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat.

Zolpidem [N,N-6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide] administered as the hemitartrate salt has proven to be an effective hypnotic agent in animals and humans. This study describes the pharmacokinetic behavior of zolpidem in plasma and brain of rat after i.v. and p.o. administration of 2.63 mg.kg-1 of [14C]zolpidem (dose expressed as the base). Autoradiography was used to examine the regional distribution of the compound and the metabolic profile of zolpidem in the plasma and brain was also investigated. The pharmacokinetic data were related to electrocorticogram power spectral analysis. After i.v. administration, the disappearance of zolpidem from plasma fitted a biexponential model with a rapid phase of 0.2 to 0.3 hr and a slower phase of 1.3 to 1.5 hr. After p.o. dosing, peak plasma concentrations where already attained at 15 min (first sampling time). Independent of the route of administration, the concentrations of zolpidem in the brain at shorter times were 30 to 50% those of the plasma values. Furthermore, up to 1 hr, zolpidem accounted for 80 to 90% of brain radioactivity. The rate of disappearance from brain paralleled that from plasma. Autoradiographic studies confirmed the rapid absorption and elimination of zolpidem as well as the relatively homogenous distribution throughout the brain. Electrocorticogram analysis in immobilized rats after i.v. administration of zolpidem showed a rapid onset and a short-acting sedative effect compatible with the kinetic profile of the parent compound. Metabolites of zolpidem displayed a poor penetration into the brain and no significant hypnotic activity. At the dose of zolpidem used, no alteration of the sleep pattern was observed.

Animals↗
PubMed1987

Correlation between reversed-phase high-performance liquid chromatography and plasma protein binding.

As hydrophobic interactions are involved in both reversed-phase liquid chromatography and plasma protein binding, the relationship between retention time and binding was investigated experimentally in two series of compounds. For betaxolol and its O-alkyl analogues, the nature of the O-alkyl group strongly influences the retention time on a Spherisorb CN 5-microns column. With 0.03 M acetate buffer (pH 5.6)-acetonitrile (60:40) as the mobile phase, k' values increase from 1.8 to 8.3 with a concomitant increase in plasma protein binding from 0.5% (R = H) to 88.2% (R = cyclopentylmethyl). The relationship between the free fraction and log k' is sigmoidal. In the second example, structural changes in the propyl side-chain of alpidem (a new anxiolytic) lead to minor variations in the protein binding: 98.9 to 84.9%. This slight decrease with the more polar metabolite is correlated with a sharp decrease in the k' values from 14.7 to 0.94 on a Supelcosil LC 18 DB column. Based on retention times, it should be feasible to predict qualitatively, if not quantitatively in some instances, plasma protein binding in a series of structurally similar compounds.

Adrenergic beta-Antagonists↗
PubMed1986

High-performance liquid chromatographic determination of alfuzosin in biological fluids with fluorimetric detection and large-volume injection.

A high-performance liquid chromatographic method has been developed for the determination of alfuzosin, a new antagonist of alpha 1 post-synaptic adrenergic receptors, in blood, plasma or urine. With fluorimetric detection and the large volume injection technique, the limit of detection in plasma is 0.5-1 ng ml-1, which is sensitive enough for pharmacokinetic studies in man. The calibration graph is linear between 1 and 200 ng ml-1 in blood plasma, with coefficients of variation of 6.2 and 1%, respectively. In urine, the linearity range is 0.05-10 micrograms ml-1; at the lowest concentration, the coefficient of variation is about 10%. A constant plasma/blood concentration ratio (1.25 +/- 0.05) allows the measurement of drug in either fluid. In blood or plasma, alfuzosin is stable at 37 degrees C for 24 h and at -20 degrees C for 6 months. As expected for reversed-phase chromatography, the retention times of alfuzosin and a few of its analogues decrease inversely with the concentration of acetonitrile in the mobile phase. However, as this concentration reaches about 75%, the retention times increase sharply. This U-shaped curve may be explained by interactions of the amino groups with silanol groups of the stationary phase.

Adrenergic alpha-Antagonists↗
PubMed1985

Determination of antiepileptic drugs.

The present paper reviews gas and liquid chromatographic methods for the determination of the most commonly monitored antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, valproic acid and clonazepam along with a new compound, progabide. The individual classes of drugs are first treated separately to highlight specific aspects of their quantification, and this is followed by an overview of those methods permitting the concomitant analysis of two or more antiepileptic compounds. Sample preparation techniques as well as comparisons between chromatographic and other techniques are treated more fully in separate sections.

Anticonvulsants↗