Antinociceptive activity of metapramine in mice. Relationship with its pharmacokinetic properties.

The antinociceptive effect of acutely and chronically (every brain elimination half-life time) administered metapramine, a tricyclic antidepressant without anticholinergic or cardiotoxic effects, was studied in three different pain tests. In the hot plate test, its action was more potent when jumping was used as a pain parameter (acute ED50 = 19 +/- 3 mg/kg, i.p.) than when pain was assessed by licking of forepaws (only 20 mg/kg, i.p. was weakly active). Five chronic doses of 15 mg/kg were as active in the tail-flick test as an acute dose of 20 mg/kg (only active dose). Metapramine was more effective in the PBQ-induced writhing test after acute (ED50 = 9.9 +/- 0.1 mg/kg, i.p.) and chronic administration. A significant linear correlation was found between the effect in this test and plasma and overall brain levels of metapramine. No correlation was observed with levels of its three desmethylated metabolites. The usefullness of using a well-defined pattern of administration based on pharmacokinetic parameters and the involvement of monoaminergic mechanisms and of some metabolites of metapramine are discussed.

[Salsolinol, an endogenous molecule. Possible implications in alcoholism, Parkinson's disease and pain]. / Le salsolinol, molécule endogène. Possibles implications dans l'alcoolisme, la maladie de Parkinson et la douleur.

Salsolinol can be formed either by condensation of dopamine with acetaldehyde, or by condensation of dopamine with pyruvic acid followed by decarboxylation. Salsolinol has a complex pharmacologic profile. Its opium-like activity may be related to alcohol dependency and to the effectiveness of naloxone during acute alcohol intoxication. Because they had noticed that alcoholism and Parkinson's disease rarely coexist, the authors undertook a study to confirm this fact and attempt to explain it by implicating salsolinol. Urinary excretion of salsolinol was found to increase following ingestion of alcohol, as well as in Parkinson patients under L-dopa treatment. The authors also found that urinary salsolinol was very low in untreated patients with Parkinson's disease. Salsolinol was detected in a number of foods and beverages. Separate assays of enantiomeres showed that the S enantiomere predominates in some foods whereas the R enantiomere is more abundant in humans. Lastly, the antinociceptive effects of salsolinol and its enantiomeres were studied in mice and antidepressant effects were evidenced using predictive tests.

Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man.

The bioavailability of two oral formulations of trimipramine, tablets and solution, was performed in twelve healthy volunteers, in a cross-over study. Each formulation was administered in the morning after a fasted period, and in the evening after a meal, in order to evaluate the role of both administration time and food consumption on the plasma kinetic parameters, under usual therapeutic conditions. A high interindividual variability of data was found. First, the extent of bioavailability was identical for the two formulations but the rate of bioavailability seemed to be different, with the p.o. solution, being more rapidly absorbed (tmax = 1.50 h). The effect of administration time was more obvious for the solution as shown by a lower quantitative absorption as well as a delay in time to reach the maximal concentration. Regardless of formulation and administration time, the t1/2 beta was about 10 hours and the mean MRT value was 11 hours.

Pharmacokinetics of metapramine and its demethylated metabolites in plasma and brain of mice.

Previous studies on pharmacokinetic parameters of tricyclic antidepressants (TCAs) in rodents have shown different results from those obtained for the same drugs in man. The kinetics of metapramine (META) and its major demethylated metabolites (METs) were studied in the SWISS CD 1 mouse after acute administration in order to establish the pharmacokinetic parameters in plasma and brain. The plasma half-life (T1/2) was very short (87 min) compared with the half-life (7 h) in man. The metabolism of META was intensive as was the transfer of META and its metabolites into the brain. The kinetic profiles of the substances were quite similar both in plasma and in brain, namely a bicompartment open model. META was rapidly absorbed (Tmax = 10 min) into and quickly eliminated (T 1/2 = 40 min) from the brain. These parameters were used to schedule sampling (blood and brain) at the appropriate time after acute administration of increased doses. The administered doses were significantly correlated to firstly the plasma or brain levels of META, secondly the plasma levels of the main monodemethylated metabolite (MET I), and thirdly the plasma or brain levels of META + METs. Finally, the evolution of plasma and brain levels of the substances was studied after repeated injections (i.e. every 40 min) and confirmed the high affinity of META and its metabolites for the brain regions.

Kinetics of metapramine and its demethylated metabolites after single and chronic oral administration in man.

The kinetics of metapramine and two of its demethylated metabolites were determined in six normal subjects after oral administration of a single 150 mg dose on day 1 and 3 X 50 mg dose on day 2-6. This study has shown that three demethylated metabolites are found in plasma beside metapramine. The monodemethylated metabolite I appeared to be the predominant one and the mean area under the plasma concentration curve (AUCo24) was 49% of the metapramine value. Its half-life was shorter (5.92 h) than that of metapramine (8.29 h). The kinetic profiles of metapramine and its major metabolites I and II were similar and data over 24 h could be fitted by a tri-exponential equation even though entero-hepatic cycles were observed. A high interindividual variability of data was found for both metapramine and its metabolites. There were no significant differences between men and women. The minimal plasma level (Cmin) seemed in agreement with the half-life of the drug.

Simultaneous determination of metapramine and its demethylated metabolites in plasma by gas chromatography-mass spectrometry.

A capillary column gas chromatography--mass fragmentographic method for metapramine and its three major demethylated metabolites is described. Compounds are extracted from plasma using a double-extraction procedure and transformed into N-trifluoroacetyl derivatives. The detection is performed by monitoring specific ions for metapramine and for its metabolites with a mass detector. In spite of extensive metabolism in the liver and rapid elimination of metapramine, plasma concentrations of both metapramine and its metabolites can be simultaneously followed over 24 h after a single 150-mg oral dose, because of the sensitivity and selectivity of the method. This method has been successfully applied to the analysis of samples obtained from patients who were at steady state with metapramine and to a pharmacokinetic study in a healthy volunteer.