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M Bialer

Publications and source records attributed to M Bialer.

At least 91 records · Page 5Linked to original sources
PubMed1990

Identification of glucose conjugates as major urinary metabolites of cannabidiol in the dog.

1. Three dogs were treated i.v. with cannabidiol (CBD) and urine collected at intervals to 30 h. 2. Metabolites were extracted, converted into trimethylsilyl (TMS) derivatives and examined by g.l.c.-mass spectrometry. 3. The major metabolites excreted at early times were identified as the phenol glucosides of 4"-hydroxy-CBD, 5"-hydroxy-CBD and 6-oxo-CBD. 4. These three oxidized metabolites were not found unconjugated, and none of the free oxidized metabolites in urine were found conjugated with glucose. 5. The conjugates were hydrolysed by beta-glucuronidase Type HP-2 from Helix pomatia and acid phosphatase but not by beta-glucuronidase Type VII from E. coli. Differential reactivity towards alpha- and beta-glucosidase indicated that they possessed the beta-configuration.

Animals↗
PubMed1989

Structure-pharmacokinetic relationships in a series of valpromide derivatives with antiepileptic activity.

The following valpromide (VPD) derivatives were synthesized and their structure-pharmacokinetic relationships explored: ethylbutylacetamide (EBD), methylpentylacetamide (MPD), propylisopropylacetamide (PID), and propylallylacetamide (PAD). In addition, the anticonvulsant activity of these compounds was evaluated and compared to that of VPD, valnoctamide (VCD), and valproic acid (VPA). MPD, the least-branched compound had the largest clearance and shortest half-life of all the amides investigated and was the least active. All other amides had similar pharmacokinetic parameters. Unlike the other amides, PID and VCD did not metabolize to their respective homologous acids and were the most active compounds. Our study showed that these amides need an unsubstituted beta position in their aliphatic side chain in order to biotransform to their homologous acids. An amide which is not metabolized is more potent as an anticonvulsant than its biotransformed isomer. All amides were more active than their respective homologous acids. In this particular series of aliphatic amides, which were derived from short-branched fatty acids, the anticonvulsant activity was affected by the pharmacokinetics in general and by the biotransformation of the amide to its homologous acid in particular. This amide-acid biotransformation appeared to be dependent upon the chemical structure, especially upon the substitution at position beta of the molecule.

Acetamides↗
PubMed1988

Pharmacokinetics of a valpromide isomer, valnoctamide, in dogs.

Valnoctamide (2-ethyl-3-methylpentanamide; VCD), an isomer of valpromide possessing both anxiolytic and antiepileptic properties, has been used as a tranquilizer in the treatment of anxiety and tension. As VCD is an isomer of valpromide (VPD), which is used both as an antiepileptic and an antipsychotic agent, we wanted to ascertain whether any differences in their pharmacological activity could be explained by pharmacokinetics. The pharmacokinetics of VCD have been studied in dogs following iv and oral administration (400 mg). Following iv administration, VCD was rapidly distributed and plasma levels declined in a biphasic fashion. The mean terminal half-life of VCD was 1.9 +/- 0.5 h and the total body clearance was 3.0 +/- 0.8 L/h. This clearance value, after normalization to blood clearance, was only approximately 10% of the hepatic blood flow. This fact indicates that the extraction ratio (E) of VCD by the liver is low, and that this drug has a restrictive clearance. The volume of distribution of VCD was within the value of the total body water. Following oral administration, the absolute bioavailability of VCD was 94 +/- 14%, and the terminal half-life was similar to that obtained after iv administration. The absolute bioavailability value thus shows that, upon oral administration, VCD is completely absorbed and does not undergo a first-pass effect. The pharmacokinetics of VCD was shown to be similar to that of VPD. The major difference was that VCD was completely absorbed and was not biotransformed to its homologous acid.

Administration, Oral↗
PubMed1988

Pharmacokinetics and protein binding of trichothecene mycotoxins, T-2 toxin and HT-2 toxin, in dogs.

The pharmacokinetics of T-2 toxin, following i.m. and i.v. administration (0.4 mg/kg), were investigated in five dogs. Following i.m. administration, the mean pharmacokinetic parameters for T-2 and HT-2 toxins were, respectively: apparent half-life 21 +/- 5 and 73 +/- 7 min; peak plasma concentration 182 +/- 42 and 74 +/- 16 ng/ml; time to reach peak plasma concentration 9.4 +/- 6.4 and 49 +/- 11 min. Mean residence time calculation, using moment analysis, showed that the terminal slope of T-2 toxin plasma levels following i.m. administration corresponds to the absorption rate constant of the toxin due to the flip-flop phenomenon. T-2 toxin was completely absorbed following i.m. administration and its absolute bioavailability was 1.17 +/- 0.25. A plasma protein binding study showed that in a concentration range of 70-500 ng/ml, T-2 and HT-2 toxins have a mean free fraction of 30.6 +/- 3.1% and 32.6 +/- 3.6% with no concentration dependency. At physiological conditions (temperature and pH), both T-2 and HT-2 toxins were unstable in whole blood and their in vitro stability half-lives were 6.9 and 0.84 hr, respectively. However, under similar conditions, these toxins were stable in plasma for 7 hr. Their instability in whole blood, therefore, may be related to enzymes present in the blood cells.

Animals↗
PubMed1988

Pharmacokinetic model of circulating covalent aggregates of insulin.

Covalent aggregates of insulin in blood of insulin-treated diabetic patients account for as much as 70% (mean 28 +/- 3.6%) of serum insulin immunoreactivity. These aggregates may originate in therapeutic insulin, because similar substances account for 0.1-3% of these preparations. Larger amounts in blood imply that aggregates accumulate as a result of delayed clearance. To test and quantify this speculation, we calculated the plasma kinetics of this material in four normal volunteers who received large intravenous doses (30 mU.kg-1.min-1) of beef-pork crystalline zinc insulin for 120 min. Insulin aggregate and monomer concentrations were measured in blood samples obtained at regular intervals throughout the infusion and during 4 h after discontinuation of insulin. Pharmacokinetic parameters were calculated from the data. Insulin aggregate and monomer serum t 1/2 were 63.6 +/- 6.9 and 34.3 +/- 2.8 min, respectively, and clearances were 101 +/- 10 and 232 +/- 47 ml/min. Volume of distribution (V beta) and volume at steady state (Vss) were 9.1 +/- 1.8 and 8.2 +/- 2.2 L for insulin aggregate and 11.6 +/- 2.8 and 12.2 +/- 3.6 L for insulin monomer, respectively. Mean residency time was 141 +/- 14 and 114 +/- 10 min for insulin aggregate and monomer, respectively [P less than .01 for all parameters except V beta (.014) and Vss (.012), aggregate vs. monomer]. Thus, in relation to insulin monomer, calculated pharmacokinetic parameters of the aggregate predict accumulation after insulin injection. Plasma t 1/2 of the aggregate was almost double that of monomeric insulin; total-body clearance and the corresponding volumes of distribution were smaller.

Adult↗
PubMed1987

Dose-dependent pharmacokinetics of a new oral cephalosporin, cefixime, in the dog.

Cefixime (CL 284,635; FK 027) is a new third-generation oral cephalosporin. To study dose-dependent pharmacokinetics of cefixime in dogs, two balanced four-way crossover studies were conducted. In the first study, oral doses of 50, 100, and 200 mg/kg and an intravenous dose of 50 mg/kg cefixime were administered. In the second study, oral doses of 6.25, 12.5, and 25 mg/kg and an intravenous dose of 12.5 mg/kg cefixime were administered to the same dogs. A period of 1 month separated the two studies. When the two intravenous doses were compared (i.e., 12.5 and 50 mg/kg), a twofold increase in clearance and volume of distribution was observed after the higher dose. The oral systemic bioavailability in the dose range 6.25-50 mg/kg was 55%. It decreased to 44% at 100 mg/kg and 27% at 200 mg/kg. The average peak serum concentrations ranged from 15.8 micrograms/ml at 6.25 mg/kg to 119 micrograms/ml at 200 mg/kg. Within this concentration range, the fraction of free drug in serum (unbound to proteins) increased from 7 to 25%. This concentration-dependent protein binding was primarily responsible for changes in total clearance, volume of distribution, and bioavailability of the drug in dogs.

Administration, Oral↗
PubMed1987

Pharmacokinetics of T-2 tetraol, a urinary metabolite of the trichothecene mycotoxin, T-2 toxin, in dog.

1. The urinary metabolites of T-2 toxin were identified and analysed quantitatively after i.v. administration to dogs. 2. A new routine assay for T-2 tetraol was developed and a pharmacokinetic study was carried out on this final hydrolytic metabolite of T-2 toxin. T-2 tetraol was excreted in urine for 2-3 days. Its 'sigma minus' plot demonstrated a significantly longer apparent half-life than its precursors (T-2 toxin and HT-2 toxin). This fact was explained by extraplasma binding causing prolongation of the metabolism and excretion of T-2 toxin metabolites. 3. The urinary metabolites of T-2 toxin were: HT-2 toxin, T-2 triol and T-2 tetraol. The metabolites were excreted in free and conjugated forms. In two dogs T-2 toxin was found in the urine in an amount which accounts for 3.2 and 16% of the administered dose respectively. The cumulative amount of the identified metabolites and toxins formed in the urine ranged from 9.7 to 17.3% in four dogs and 44.7% in one dog.

Animals↗
PubMed1987

Pharmacokinetics of cefixime after oral and intravenous doses in dogs: bioavailability assessment for a drug showing nonlinear serum protein binding.

Cefixime is a new oral cephalosporin which shows dose dependent absorption and concentration dependent serum protein binding in dogs. To study the absolute bioavailability of this drug in dogs, intravenous infusions of 6.25 and 25 mg/kg (each given over 2 hours), approximating the rate of appearance of the drug also given after oral dosing (12.5 and 50 mg/kg) were administered on separate occasions. The mean respective pharmacokinetic parameters obtained after the two intravenous infusions (6.25 and 25 mg/kg) were: total body clearance 4.0 and 5.2 mL/min; volume of distribution 2.2 and 2.8 L; and terminal half-lives of 6.4 hrs. Serum concentrations and area under the serum concentration time curve (AUC) after the low intravenous and oral dose were similar. At the higher doses, serum concentrations and AUC values were significantly higher after the intravenous infusion than after the oral dose. The mean absolute bioavailability (F) values after the 12.5 and 50 mg/kg oral doses using serum AUC comparisons were 52 and 58%, respectively, when calculated against the 6.25 mg/kg intravenous dose and 73 and 38%, respectively, when calculated against the 25 mg/kg intravenous dose. Based on urinary recovery data, F was 49 or 43% for the 12.5 mg/kg oral dose and 34 or 30% for the 50 mg/kg oral dose, depending on the reference intravenous dose used. These results show that because of nonlinearities in the pharmacokinetics of cefixime in the dog, comparison of AUC values obtained after oral doses to AUC values derived following intravenous administration of the drug may result in inaccurate bioavailability estimates if the concentration ranges after the two routes of administration are substantially different. Since the clearance of the drug is concentration-dependent, the absolute bioavailability of the drug must, therefore, be estimated under conditions where serum concentrations obtained after oral and intravenous doses are similar. In summary, for a drug like cefixime which shows nonlinear pharmacokinetics in the dog, estimations of absolute bioavailability, can be more accurately made using urinary excretion data.

Administration, Oral↗
PubMed1986

New, sensitive thin-layer chromatographic-high-performance liquid chromatographic method for detection of trichothecene mycotoxins.

Diphenylindenone sulphonyl (Dis) esters of trichothecene mycotoxins when sprayed with sodium methoxide showed fluorescent spots on a thin layer of silica gel when viewed under long-wavelength UV light. The detection limit for trichothecene esters in thin-layer chromatography (TLC) was 20-25 ng per spot for T-2 toxin, HT-2 toxin, diacetoxyscirpenol, T-2 triol, T-2 tetraol and iso-HT-2 toxin. A quantitative high-performance liquid chromatographic (HPLC) analysis of Dis-trichothecene esters was also developed using UV detection at 278 nm. The detection limit for the above esters varied between 30 and 50 ng per injection. This sensitive TLC-HPLC method is very useful for in vivo pharmacokinetic analyses of trichothecenes.

Chromatography, High Pressure Liquid↗
PubMed1985

Gas chromatographic assay with pharmacokinetic applications for monitoring T-2 and HT-2 toxins in plasma.

A gas-liquid chromatographic (GLC) method for monitoring T-2 and HT-2 toxins in plasma was developed. The procedure involved extraction of the toxins with ethyl acetate, chromatography on a C18 reversed-phase column and derivatization with heptafluorobutyric anhydride (HFBA). The T-2 and HT-2 HFBA derivatives were chromatographed on OV-17 at various temperatures and measured with an electron-capture detector. Iso-T-2 toxin and iso-HT-2 toxin were used as internal standards. Recoveries averaged 95.1 +/- 8.6% for T-2 toxin and 102.1 +/- 5.2% for HT-2 toxin at levels ranging from 40 to 120 ng/ml. The limits of detection were 30 and 5 ng/ml of T-2 and HT-2 toxin, respectively. The range of the assay covers plasma concentrations at which toxicity becomes manifest. The pharmacokinetic application of this GLC method is illustrated by simultaneous monitoring of T-2 and HT-2 toxins levels in plasma obtained after intravenous administration of T-2 toxin to a dog.

Animals↗
PubMed1985

Effect of sustained-release on the pharmacokinetics of theophylline in healthy subjects.

The effect of sustained-release on the pharmacokinetics of theophylline was examined by comparing two sustained-release formulations (Theo-Dur and Theotard) to an oral solution and i.v. preparation of the drug. Drug-level monitoring was performed by an HPLC assay. The absorption profiles of the three oral formulations were pharmacokinetically analyzed by using the Loo-Riegelman procedure. The absorption of theophylline after the administration of the Theo-Dur and Theotard was found to be of an apparent zero-order kinetics.

Adult↗
PubMed1984

Rapid gas chromatographic assay for monitoring valproic acid and valpromide in plasma.

A gas chromatographic (GC) method for monitoring valproic acid and valpromide in plasma was developed. The procedure involved a single solvent extraction of drugs from acidified plasma samples, followed by a GC injection of the organic phase. This rapid, sensitive, specific, and reproducible method is a key factor in pharmacokinetic and stability studies of valpromide. Pharmacokinetic application of the new GC method is presented by a simultaneous plasma monitoring of valpromide and valproic acid levels obtained after intravenous administration of valpromide to a dog.

Chromatography, Gas↗
PubMed1984

Comparative pharmacokinetic analysis of a novel sustained-release dosage form of theophylline in humans.

The pharmacokinetics and relative bioavailability of theophylline from a new sustained-release formulation ( Theotard ) and from a standard sustained-release formulation (Theo-Dur) were compared in 6 healthy, adult, male volunteers. After a single oral dose of 300 mg Theotard , a mean maximal plasma concentration ( Cbmax of 3.49 +/- 1.05 mg/l was obtained after 8 h (tmax). After an identical dose of Theo-Dur, a peak plasma concentration of 4.68 +/- 1.33 mg/l was obtained after 6.33 h. The mean relative bioavailability of theophylline from Theotard was 1.02 +/- 0.16 relative to that of Theo-Dur. In 5 of the volunteers the Theotard formulation exhibited a more prolonged and uniform absorption rate and yielded more sustained plasma levels.

Adult↗
PubMed1984

Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers.

The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79 +/- 0.24 and 0.77 +/- 0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, nonhygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.

Adult↗
PubMed1984

Isolation of a cigarette smoke fraction responsible for the inhibition of benzo[a]pyrene metabolism in the isolated perfused rabbit lung.

Among the several thousand components of cigarette smoke is a substance or substances capable of inhibiting pulmonary metabolism of nicotine and altering the metabolite profile of procarcinogens such as benzo[a]pyrene (BP). This substance(s) inhibits BP metabolism in the lung in amounts present in a few puffs of cigarette smoke. By a series of extractions and chromatographic methods an active subfraction containing only 1% of the total cigarette smoke condensate (CSC), was isolated. This fraction demonstrated the same inhibition of BP metabolism in the isolate perfused lung (IPL) as the whole smoke. The inhibitor(s) present in this fraction possess amphoteric characteristics. The acidic function is believed to be a phenolic one.

Animals↗