Accumulation of apomorphine in caudate nucleus and hippocampus of the rabbit.

Apomorphine concentration was assayed in the caudate nucleus, hippocampus and cerebellum of rabbits injected with various doses of the drug 30 min earlier. Apomorphine accumulation was dose-dependent but uneven in the structures tested: the accumulation in the caudate nucleus being approx. 5 times higher than in cerebellum. Pretreatment with haloperidol significantly depressed the accumulation of apomorphine in the caudate nucleus and hippocampus, but not in the cerebellum. The amount of apomorphine displaceable by haloperidol was approx. 10 times higher in the caudate nucleus than in the hippocampus. The results suggest the existence of small number of apomorphine binding sites in the hippocampus.

Effect of dosage and route of administration of trazodone on cerebral concentration of 1-m-chlorophenylpiperazine in rats. Kinetics of trazodone biotransformation in rats.

The levels of trazodone (TRZ) and its metabolite, 1-m-chlorophenylpiperazine (CPP) in the rat brain were tested after single and multiple administration of TRZ ip or po. After a single oral dose and after multiple ip or po administration of TRZ, the brain level of CPP exceeded markedly that of the parent compound. Some of pharmacokinetic parameters of TRZ and CPP were significantly changed after chronic treatment. As the biological effect of CPP is opposite to that of its parent compound, the high level of metabolite in the central nervous system may affect strongly the pharmacological activity of TRZ.

Effects of some antidepressant drugs on apomorphine concentration in the central nervous system of rats and apomorphine-induced stereotypy.

Pharmacokinetic aspects of interaction between antidepressant drugs (AD) and apomorphine (APO) have been studied. It was found that neither acute nor chronic AD pretreatment affected the distribution of APO-induced stereotypy was not changed. An exception was citalopram (CIT) which given in a single dose to rats significantly potentiated APO-induced gnawing. Single dose of investigated AD delayed the onset of APO-induced sniffing, licking and gnawing, however the overall effect did not reach the statistically significant level. The presented results suggest that changes of APO behavioral effects induced by AD pretreatment are rather due to pharmacodynamic and not pharmacokinetic interaction.

Preliminary study of the biotransformation of two new drugs, trazodone and etoperidone.

M-Chlorophenylpiperazine (CPP) is formed in the course of biotransformation of trazodone and etoperidone. The biotransformation of the latter compound is more rapid. An enzymatic inhibitor, proadifen (SKF 525A), inhibited the formation of CPP, while an enzymatic inductor, phenobarbital, did not affect it. The elimination rate of CPP was much lower than that of trazodone; its t0.5 was approx. 50-60 min. The pharmacokinetic data may explain well the pharmacological properties of trazodone and etoperidone.

Pharmacokinetics of trazodone after different routes of administration.

Pharmacokinetics study of trazodone after iv, ip and po administration has been performed in rats. Trazodone was given to animals in a single or multiple doses of 20 mg/kg p. o. or ip, or in doses of 5 and 10 mg/kg iv. The levels of the drug in plasma and brain tissue were assayed spectrofluorometrically at predetermined time intervals. The results indicate that neither the route of administration nor the dosage schedule affects in significant manner the pharmacokinetics of trazodone, but the pharmacokinetic parameters depend upon the dose used. The affinity of the drug to blood and brain tissue is nearly the same, in contrast to imipramine which shows, a low affinity to blood and high affinity to brain tissue.

A spectrophotometric method for N-nicotinoyl-tryptamine (tryptamide) assay in the blood serum of rats.

A spectrophotometric method for N-nicotinoyl-tryptamine (tryptamide) (TR) assay in the blood serum of rats has been elaborated. Sensitivity of the method is approx. 1 microgram of TR/ml of blood serum, recovery approx. 76%. Using this method a preliminary pharmacokinetic study of TR was carried out in rats after ip or po administration of different doses of TR. It was found that the total amount of TR, expressed as corresponding AUC values, was nearly the same after both routes of administration of the same dose of TR. In addition, an effect of two solubilizing agents, 1% Tween 80 and gum arabic on TR (free base or hydrochloride) absorption from gastrointestinal tract of rats into general circulation has been investigated. Results of this study indicated the best absorption of TR when the substance, was given to rats as a hydrochloride suspended in 1% Tween 80 solution.

Distribution of citalopram in the blood serum and in the central nervous system of rats after single and multiple dosage.

Distribution in rat tissues of citalopram, a potent and specific inhibitor of neuronal 5-HT uptake was uneven. The blood serum level of the drug did not reflect its distribution in the brain tissue and in the spinal cord. Prolonged administration of citalopram enhanced its blood serum, brain and spinal cord AUC values and slowed down its elimination from all investigated tissues. In contrast to imipramine, citalopram penetrated easily to the spinal cord.

Chronic dosage of imipramine in animal experiment: concentrations of imipramine and desipramine in the rat brain after various modes of dosage.

Concentrations of imipramine (IMI) and desipramine (DMI) in the rat brain after administration of IMI in aqueous solution by stomach gauge twice daily, in oil solution parenterally at 48 h intervals, and with drinking water were assayed. IMI administration with the drinking water for 21 days produced a pattern of the brain concentrations of IMI and DMI similar to that observed in rats receiving IMI by stomach tube for two weeks, at 12 h intervals. When IMI was given to rats ip in an oil solution at 48 h intervals for 10 days, the brain levels of both IMI and DMI were very high and rather stable during 48 h after administration of the last dose of IMI. However, the relation between brain concentration of IMI and DMI differed markedly from that found in rats receiving IMI with the drinking water. It seems that administration of IMI with drinking water may be recommended as a reliable and convenient dosage schedule in experiments which need prolonged treatment with IMI.

On-line diode array UV-visible spectrometry in screening for drugs and drug metabolites by high-performance liquid chromatography.

The direct coupling of a multi-channel diode array UV-visible spectrophotometer to a powerful reversed-phase HPLC separation system is considered, especially for use in qualitative analysis, e.g., screening/identification of drugs and drug metabolites. The approach is illustrated by the screening for metabolites of butoprozine and ticlopidine directly in human and rat bile.