Pepsin immobilized by covalent fixation to hydroxyalkyl methacrylate gels: preparation and characterization.

Insoluble active derivatives of pepsin (EC 3.4.23.1) were prepared by covalent binding of this enzyme to hydroxyalkyl methacrylate gels modified with 1,6-diaminohexane or epsilon-aminocaproic acid in an acid medium by means of water-soluble carbodiimide. The amount of attached enzyme, its proteolytic activity, pH activity curves of the preparations obtained and the time and pH dependence of their stability were determined.

Pharmacokinetics and brain entry of alaptide, a novel nootropic agent, in mice, rats and rabbits.

Pharmacokinetics of a novel nootropic agent, alaptide, have been examined in plasma and brain of mice, rats and rabbits following an intravenous dose (1 mg kg-1). First-order equilibration rate constants between plasma and brain (kBO) were calculated by a two-compartment model with a linked compartment (brain). Brain alaptide equilibrates rapidly with the central compartment in mice and rats due to the high kBO/beta ratio. In rabbits the equilibration is much slower (kBO/beta approximately 1). Partition coefficients between brain and plasma calculated from areas under the brain and plasma concentration-time curves, are 0.479, 0.549 and 0.864, in mice, rats and rabbits, respectively.

Bioavailability of two oral formulations of triazolam using radioreceptor assay.

The radioreceptor assay (RRA) was used to quantitate plasma triazolam concentrations in eight female volunteers following single 0.5 mg doses of two tablet formulations in a cross-over study. Bioavailability in terms of area under the plasma concentration versus time curve (AUC0 infinity), maximum plasma concentration (Cmax), time to maximum (tmax), and mean residence time (MRT) was not statistically significantly different from one formulation to the other.

Disposition of [3H]cloflumide, a new neuroleptic drug, in rats.

The disposition of cloflumide (VUFB 15496), 2-chloro-7-fluoro-10 [4-(carbamoylethyl)piperazino]-10,11-dihydrodibenzo [b,f] thiepin methansulfonate, a new neuroleptic agent, following single oral and intravenous dose was studied in the rat using radiotracer techniques. [3H]Cloflumide was almost completely absorbed from the gastrointestinal tract; peak plasma levels of the parent drug were attained within 4 h of oral drug administration. The mean residence time of the unchanged drug was 2.75 h after intravenous administration. The total neuroleptic activity in plasma determined by radioreceptor assay paralleled with plasma cloflumide level indicating that the dopamine inhibiting action is mediated solely by the parent drug. Concentration of radioactive substances was high in the liver and kidneys; in the brain was slightly higher than blood level. Total radioactive meterial as well as unchanged cloflumide were mostly excreted in feces (87 and 10%, respectively). At 3 days postdosing, 96% of the administered dose was recovered.

Pharmacokinetics and metabolism of [3H]-pipethiaden in healthy volunteers.

Six healthy volunteers participated in a single-dose study of pharmacokinetics and metabolism of oral administration of [3H]-pipethiaden (1 mg). Plasma levels of total radioactivity, urinary excretion and metabolism were analyzed by liquid scintillation counting and radio-TLC. The mean peak plasma concentration of radioactive metabolites was 4.9 ng eq/ml, and the mean elimination half life was 11.5 h. 34% of radioactivity was recovered in 4 days in urine, with only 0.4% present as unchanged drug. Pipethiaden was extensively metabolized by S-oxidation, N-demethylation, and N-oxidation.

Pharmacokinetics of 3H-pipethiaden after single oral and intravenous administration in rats.

Tritium labelled anti-migraine drug 4-(1-methyl-4-piperidyliden)-4,9-dihydrothieno[2,3-c]-2-b enzothiepine (pipethiaden) was prepared. After oral and intravenous administration to rats not only the courses of total radioactivity in plasma and various organs were determined, but by means of TLC-radiometry also the levels of pipethiaden itself. After the oral dose 1.35 mg/kg the plasma levels of pipethiaden did not exceed 3.5 ng/ml. Some pharmacokinetic parameters (e.g. t1/2 el-4 h) were calculated by compartmental analysis of plasma levels.

[Disposition of the potential antidepressive agent (3H) VUFB 15468 in mice and rats]. / Dispozice potenciálního antidepresíva (3H) VUFB 15468 u mysí a krys.

Excretion, biodistribution and pharmacokinetics of the above-mentioned drug after oral doses of 10 and 50 mg/kg were investigated. The drug is completely and rapidly resorbed from the digestive tract. It shows relatively large renal and metabolic clearance, it is extensively distributed in the tissues This results in its rapid elimination from plasma (t1/2 approximately 3 h) and, on the other hand, higher concentrations of radioactive drugs in tissues. Penetration and specific binding of VUFB 15468 in the murine brain in dependence on the administered dose were tested (ED50 approximately 4 mg/kg). Autoradiographic examination of the rat brain demonstrated an increased concentration of radioactive drugs in the cerebral cortex, hippocampus, hypophysis and central ganglia.

Pharmacokinetics of flobufen and its main active metabolite in the rat.

Pharmacokinetic study of the anti-inflammatory [3H] flobufen (I) and its active metabolite (II) has been carried out in rats given po and iv doses of 2, 10, and 50 mg/kg I and equimolar doses of II. Various pharmacokinetic parameters of I and II [dose normalized AUC; mean residence time (MRT); systemic blood clearance; steady state volume of distribution, (Vss)] are dose-independent. I is completely absorbed from the gastrointestinal tract and is rapidly (MRT = 7.2 hr) converted to II, which is slowly (MRT = 2.6 days) eliminated from the blood. The fraction of total blood clearance that forms II is 0.83 following iv dose of I. The Vss of the less lipophilic metabolite II is somewhat lower (0.36-0.46 liters/kg) than that of the parent drug (0.51-0.56 liters/kg).

Radioreceptor assay for ergot derivatives, transdihydrolisuride and lisuride, in biological fluids.

The development of a sensitive radioreceptor assay (RRA) for transdihydrolisuride (TDHL) and lisuride, as well as the synthesis of tritiated TDHL, is described. The method is based upon the competition between 3H TDHL and TDHL or lisuride for rat brain dopaminergic receptors. Linear calibration graphs were obtained in the range of 0.2-9 pmol for an ergot derivative. Relative affinities of the main metabolites, deethylated and dideethylated on the urea part of the molecule are 3.6% and 1.5%, respectively, as compared to the parent drug. To verify the method, plasma levels of TDHL were determined in rats after oral administration.

Changes of pharmacokinetics and metabolism of sulfadimidine in endotoxin pretreated rabbits.

Changes of pharmacokinetics and acetylation of sulfadimidine (SDM) were studied in endotoxin pretreated rabbits. With increasing doses of endotoxin the levels of intravenously administered SDM were lower. The acetylation rate was reduced in urine of rabbits after medium endotoxin doses.

Pharmacokinetics of oral terguride in patients with a prolactinoma.

The pharmacokinetics of oral terguride 1 mg was evaluated in a single-dose study in 8 patients with a prolactinoma and one with acromegaly. A radioreceptor assay was used to measure the plasma levels of terguride. The peak plasma concentration (2.3 +/- 0.7 ng/ml, mean +/- SEM) was attained within 1 h of drug administration. Moment analysis gave a mean residence time of 4.3 +/- 0.6 h. Plasma prolactin was also determined by radioimmunoassay. The plasma prolactin was reduced to 30 +/- 3% of its pretreatment value after 4 h.

[Disposition of [3H]flobufen and its active metabolite in rats]. / Dispozice [3H]flobufenu a jeho aktivního metabolitu u krys.

The present authors investigated the excretion, distribution and pharmacokinetics of the novel potential antirheumatic agent flobufen and its active metabolite after p.o. and i.v. doses of 2, 10 and 50 mg/kg administered to rats. The drug is resorbed well from the digestive tract and mostly it is metabolized to the principal metabolite M, which is only slowly excreted from the organism mainly by renal clearance. Within the whole dose range the kinetics of the drug is linear. Binding of flobufen and M to proteins is high (95-99%). The highest concentrations of radioactive metabolites (mostly M) were found in the plasma, liver, lungs, kidneys, connective tissue and inflammatory foci. The penetration of metabolites through the placenta and excretion in human milk are relatively important.

[Metabolites of substance VUFB 15468 in animals]. / Metabolity látky VUFB 15468 u zvírat.

Metabolites of drug VUFB 15468 present in the urine of rats, mice and dogs and in rat faeces after peroral administration were determined qualitatively. The relative representation of the individual metabolites in the urine of rats and mice was determined radiometrically after p. o. administration of [3H]VUFB 15468. For qualitative demonstration the metabolites were extracted; they were detected, partially identified and purified by thin-layer chromatography and then analyzed by mass spectrometry and IR-spectrometry. Structures of 11 metabolites were completely or partially determined in rat urine. Five of them were also found in rat faeces, one in murine urine and five in canine urine. In all animal species also unchanged VUFB 15468 was found. For quantification of the individual metabolites and VUFB 15468, TLC-radiometry and liquid scintillation spectrometry were used in rats and mice. Of the relative representation of metabolites, about one third is unchanged VUFB 15468, the rest are metabolites. In mice, the proportion of unchanged VUFB 15468 is much higher, about two thirds.

Interspecies pharmacokinetic scaling of metazosin, a novel alpha-adrenergic antagonist.

Based on pharmacokinetic data from mice, rats, and rabbits, the prediction of pharmacokinetics of intravenous metazosin in man has been performed. The correlations were based upon allometric scaling of plasma clearance and the volume of distribution at steady-state. A one-compartment body model approximating clinical pharmacokinetics fits well the elimination phase of subsequently measured metazosin concentrations in volunteers. Fitting human pharmacokinetic data to allometric equations enabled us to superimpose pharmacokinetic curves from different species.

Pharmacokinetics and pharmacodynamics of terguride following intramuscular administration in cows and goats.

The pharmacokinetics of intramuscular terguride (transdihydrolisuride) was evaluated in a single-dose study in cows (doses 100, 62 and 31 micrograms/kg b.w.) and goats (dose 100 micrograms/kg b.w.). A radioreceptor assay was used to quantitative plasma terguride concentrations. The peak plasma concentrations of terguride were attained within 0.6 h of the drug administration and then decreased monoexponentially with half-life of 1.3 h (cows) and 2 h (goats). The pharmacokinetics of terguride in cows is nearly linear. Pharmacodynamics of terguride was expressed as reduction in plasma prolactin levels. Maximal decline in prolactin was observed 3-4 h following terguride administration and the effect lasted for about 24 h.

Pharmacokinetics and pharmacodynamics of conventional and controlled-release formulations of metipranolol in man.

The pharmacokinetics and beta-adrenoceptor blocking effects of conventional and sustained-release metipranolol have been studied in 6 healthy male volunteers given a single oral dose of 40 mg. Plasma drug concentrations determined by TLC and a radioreceptor assay, and the inhibition of exercise-induced tachycardia, were monitored for 48 h. Relevant amounts of active metabolites other than deacetylmetipranolol were not found. Compared to conventionally formulated metipranolol, the controlled-release product had a prolonged mean residence time (10.7 vs 5.5 h), the peak drug concentration was halved and the time to peak drug concentrations was delayed. Relatively constant plasma concentrations (cideal = 6.5 ng/ml) and a clinically significant reduction of exercise-induced tachycardia were maintained throughout a 24 h dosing interval. An individual deacetylmetipranolol plasma concentration-effect relationship was evaluated using the Emax model. Mean parameters were Emax 26% and C50 2.9 ng/ml.