Bioavailability study of a new amoxicillin tablet designed for several modes of oral administration.

A new tablet of amoxicillin (Flemoxin solutab) has been formulated with galenic properties which allow it to be taken as a tablet, either swallowed, chewed or sucked, or to be taken after dispersion in water. This study was undertaken to compare the bioavailability of the new tablet (swallowed as such, or after dispersion) with a commercially available amoxicillin capsule and, for purposes of internal reference, with a Flemoxin forte suspension. Each formulation was administered to 12 volunteers according to a repeated 4 X 4 latin square design. Statistical analysis revealed that the tablet and suspension formulations tested gave significantly higher maximum plasma levels, occurring significantly faster after intake, when compared to the capsule. Furthermore, the new tablet showed a statistically significantly greater area under the plasma concentration-time curve with a highly predictable absorption when compared to the capsule. The method of intake of the new tablet appeared to be of no relevance with respect to the observed bioavailability.

Bioavailability of new formulations of amoxicillin in relation to its absorption kinetics.

The newly developed amoxicillin (Flemoxin) formulations, a film-coated tablet (A) and an effervescent tablet (B) were tested for bioavailability against a commercial reference formulation (C). The content of amoxicillin in each formulation was 1000 mg. The cross-over study involved 12 healthy volunteers. Blood samples were taken at 10 time intervals after administration and plasma analysed for amoxicillin concentration by bio-assay. Numerically, the effervescent formulation had a superior mean bioavailability over both other formulations, but the difference failed to reach statistical significance due to quite large individual variations. A striking point emerging from a pharmacokinetic treatment of the data was the zero-order nature of the amoxicillin absorption. Re-evaluation of some published data on amoxicillin serum or plasma concentrations, with sufficient data points in the absorption phase, confirmed this observation. This absorption behaviour of amoxicillin is discussed. Assuming the same volume of distribution of amoxicillin for the three formulations, it could be calculated that the mean zero-order rate constant for the effervescent formulation B exceeded that for formulations A and C by a factor of 1.9 and 1.5, respectively. Thus, formulation B shows the most rapid absorption of amoxicillin in accordance with its administration in an already dissolved form.

Interaction between substituted 1-[2-(diphenylmethoxy)ethyl] piperazines and dopamine receptors.

Substituted 1-[2-(diphenylmethoxy)ethyl]piperazines were tested for their affinity to specific [3H]dopamine binding sites in membrane preparations from the corpus striatum of the rat. In particular, 4-(3-phenyl-2-prop(en)yl)- and 4-(3-phenyl-2-butyl)-substitution yielded compounds potent in displacing [3H]dopamine from its binding sites, with IC50-values in the order of 10 nM. There was a significant correlation between the IC50-values determined in this binding assay and the IC50-values obtained for the same compounds in a previous study on their potency to inhibit the uptake of dopamine in synaptosomal preparations of the striatum of the rat. Current insight in structural requirements for binding to dopamine receptors, as obtained mainly with rigid analogues of dopamine, gives no satisfactory explanation for the dopaminergic activity of the piperazine derivatives tested.

Correlation between the distribution of 3H-labelled enkephalin in rat brain and the anatomical regions involved in enkephalin-induced seizures.

The correlation between the distribution of the intraventricularly (i.v.t.) administered delta agonist [3H](D-ala2,D-leu5)-enkephalin ([3H]DADL) and the anatomical regions involved in enkephalin-induced seizures has been studied in rat by using an autoradiographic method and recording of the electromyogram (EMG) and the electroencephalogram (EEG). The results indicate that within 10 min, the radioactivity of the intraventricularly administered drug reached all parts of the ventricular system, including the central canal of the spinal cord. However, within 2.5 min after the intraventricular administration of [3H]DADL, which corresponds to the onset of DADL-induced seizures, the substance appeared mainly in the left lateral ventricle and occasionally in the third ventricle. During the first 2.5 min the substance penetrated regularly into the surrounding periventricular tissue of the striatum, septum and hippocampus to a depth of about 100 microns. The most intensive and long-lasting epileptic discharges, exceeding 30 min were observed in the hippocampus, in contrast to the mild and short-lasting electrophysiological responses of the septum and corpus striatum. The experiments suggest that the short onset of enkephalin-induced excitatory phenomena is due to the rapid distribution and penetration of the substance in the surrounding periventricular tissue. According to these data, it is proposed that activation of delta opiate receptors, localized within the first 100 microns of the periventricular tissue, mainly in the hippocampus, is essential for the triggering of endorphin-induced seizure activity.

Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man.

Plasma concentrations of orphenadrine were measured by a specific gas chromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2-20.1h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.

Pharmacological properties of colloidal bismuth subcitrate (CBS, DE-NOL).

In pharmacological ulcer models in rats colloidal bismuth subcitrate (CBS) demonstrated anti-ulcer activity. This was neither a result of an acid neutralizing nor of an acid secretion inhibitory effect. Both in vitro and in vivo, an anti-peptic action was found. At low pH CBS precipitates and was shown to form a coating on the gastric wall especially on the ulcer crater. This coating most likely forms a protective barrier to the peptic activity of gastric juice. Low toxicity was seen following chronic daily administration of high doses of CBS for 3 months to rats and 6 months to dogs. Although the blood levels were more elevated in rats, the tissue bismuth levels were comparable in the two species (except for the caecum). The chief bismuth-excreting organs, the kidneys, showed relatively high concentrations, while the brain-concentrations were extremely low in concordance with the absence of nervous system toxicity.

Sensitive and specific gas chromatographic and extraction method for the determination of orphenadrine in human body fluids.

A gas chromatographic and extraction method for the assay of orphenadrine in plasma and urine has been developed, in which diphenhydramine is used as the internal standard. The procedure involves extraction with isopentane and alkali flame ionization (nitrogen) detection. Orphenadrine N-oxide and N-dealkylated orphenadrine did not interfere with the analysis. Orphenadrine concentrations down to 1 ng/ml can be determined. Application in a pharmacokinetic/bioavailability study is reported.

Excretion and distribution studies in rats with two forms of 14carbon-labelled polyvinylpyrrolidone with a relatively low mean molecular weight after intravenous administration.

Excretion and autoradiographic distribution studies were performed in rats with two 14C-labelled polyvinylpyrrolidone preparations, both of relatively low mean molecular weight but different in molecular weight distribution. At different time intervals after i.v. administration, elimination of radioactivity was found to be more complete for the preparation with the smallest fraction of molecules having a weight of over 25000, which is approximately the weight limit for rapid glomerular filtration in the rat. Our study demonstrates that the retention of PVP in organs, which in the literature are mentioned as target organs for PVP-toxicity, can be largely prevented by decreasing the fraction of molecules with a weight of more than 25000.

Topical and systemic effects of hydrocortisone 17-butyrate.

In a series of hydrocortisone 17-esters, hydrocortisone 17-butyrate (HC-17B) has almost optimal lipophilicity resulting in a topical effect comparable to that of the fluorinated corticosteroids as measured in the McKenzie test on the human skin. In rats its systemic effects are weak, being in the order of those of hydrocortisone. In man systemic effects have been demonstrated, but no exact comparative. In man systemic effects have been demonstrated, but no exact comparative data are available. Important FACTORS controlling the intensity of systemic effects are: rate of liberation into plasma from the depot in the horny LAYER, RATE of metabolic degradation, and rate of plasma clearance. In rats the main factor seems to be rapid clearance from plasma (t 1/2 = 0.5h) by selective concentration in the liver and, to a lesser extent, in the kidneys. Rapid hydrolysis by esterases in plasma and liver plays an additional role. In man hydrolysis by esterases appears to be rather slow; the rate of clearance from plasma is still unknown, whereas the absorption from the intact skin into the blood seems to be very slow (t 1/2 = 25 h).

A combined study on the distribution of oxytetracycline and polyvinylpyrrolidone in rats.

With the purpose of studying the influence of polyvinylpyrrolidone (PVP) on the disposition of oxytetracycline (OTC), OTC was administered i.v. to male rats in two formulations, one of which contained 14C-labelled PVP. From the rats, whole-body sections (30 mum) were taken which were subjected to three analytical procedures: autoradiography to determine the distribution of the PVP-14C, fluorography and bioautography to obtain information on the OTC-distribution. The experimental results suggest equilibrium complex formation between OTC and PVP, it being mainly the complex which is i.v. injected when both products are combined in an injection formulation. Such complex formation can explain the lower toxicity of OTC when injected in combination with PVP as well as the slower build-up of OTC-levels in some organs, compared with that after OTC administration without PVP. Beyond this kinetic effect of PVP on the fate of OTC no evidence was obtained for an influence of PVP on the OTC distribution pattern per se, or on its ultimate antibiotic activity in the different organs. Some details of the OTC and especially of the PVP distribution are discussed.

Distribution of [14C]-tofenacine in rat brain after intravenous, intraperitoneal and multiple oral dosage.

The distribution of radioactivity in the rat brain at 5 min after 10 mg/kg of 14C-labelled N-methyl-2[(o-methyl-a-phenylbenzyl)oxy]ethylamine, [14C]-tofenacine-hydrochloride, the active constituent of Elamol¿ and Tofacine¿, i.v. showed a heterogeneous pattern correlating well with what is known about perfusion and capillarization of brain areas. With the passage of time total brain radioactivity decreased rapidly and radioactivity was redistributed. Both processes occurred simultaneously so that a nearly homogeneous pattern was found at 1 h after i.v. administration. The outer layers of the hippocampus were then the only brain areas with a higher concentration of radioactivity. On i.p. administration of 25 mg/kg of [14C]-tofenacine-hydrochloride maximum brain radioactivity was observed at 30 min, the distribution pattern resembling that seen at 5 min after i.v. dosage. Its further time course corresponded to that of the i.v. series. On multiple oral administration of [14C]-tofenacine-hydrochloride (4 doses of 25 mg/kg at 3-h intervals), maximal radioactivity in the rat brain was observed at 120 min after the last dose. Again the distribution was heterogeneous. Areas of high and low radioactivity were very similar to those seen in the i.v. series at the first intervals, although the contrasts were less pronounced. An exception was the hippocampus where the distribution of radioactivity, -- with high levels in the outer layers as the principal feature -- was similar to that at the last intervals after i.v. administration. A model comprising a central compartment and two brain compartments, representing areas of high and low perfusion, respectively, allows a quantitative explanation of the phenomena observed.