Miroslawa Melzacka

l-(m-Chlorophenyl)piperazine: a metabolite of trazodone isolated from rat urine

The metabolism of the psychotropic drug trazodone ~-[3-(4-(m-chlorophenyl)l-piperazinyl)-propy~]-s-triazolo-(4,3-a)-pirydin-3-(2H)one(I) has been examined in rats, rabbits and in men (Baiocchi & Frigerio 1974; Jauch et a1 1976, Yamato et a1 1974a,b, 1976a,b) with trazodone containing labelled carbon atom in the triazole ring, and metabolites were isolated by radiochromatographic methods. In the course of these studies ~-(3-oxO-s-triaz010(4,3a)pyridin-2-yl)-propi0nic acid(I1,OTPA)and its glucuronide (Yamato et al 1974b) were found in rat urine. The formation of OTPA suggested that, beside hydroxylation of ring systems (as previously found), the trazodone molecule could undergo hydrolysis and oxidation in the aliphatic chain. However, what happened to the remaining fragment of trazodone molecule containing the phenylpiperazine system (1 -(m-chloropheny1)piperazine 111, CPP) was not known because of the lack of a labelled carbon atom that could be identified by scintillation methods. Pharmacological studies of trazodone carried out in this Institute (Baran et a1 in the press, Maj et a1 1978a,b, 1979) demonstrated that this drug at low doses had a central anti-5-hydroxytryptaminergic action, while at higher doses it produced a 5-HT-ergic stimulation. The latter effect was observed about 20 min after an intravenous injection of trazodone which suggested that it might be induced not by trazodone itself but by its metabolite. Further investigation showed that OTPA, the trazodone metabolite formerly described, was inactive whereas the hypothetical metabolite CPP, not detected so far, induced 5-HT-ergic stimulation similar to that evoked by high doses of trazodone, but obserked immediately after an intravenous injection of CPP. We set out to find out whether CPP was formed in rats treated with trazodone. The experiments were on male, Wistar rats, deprived of food overnight. Trazodone (Angelini Francesco Roma, 25 mg kg-1 i.p.) or CPP (Angelini Francesco Roma, 1 mg kg-I i.p.) were administered in aqueous solution. The rats were housed in metabolic cages and their urine was collected for 24 h. The urine was divided into 1 ml samples, pH was adjusted to 8.0 with 0.05 M K,CO, and extracted with 3 ml of ethyl acetate. The acetate layer was separated (fraction F I), pH of inorganic layer was adjusted to 2 with 0 1 M HCI and extracted with acetate (fraction F 11). The acidic residue was boiled for 30 min, cooled and extrated again with ethyl acetate (fraction F 111). Then the

The effect of neuroleptics on imipramine demethylation in rat liver microsomes and imipramine and desipramine level in the rat brain

A study of the cytochrome P-450 level and imipramine (IMI) demethylase activity in liver microsomes of rats treated concurrently with IMI and chlorpromazine (CPZ) or IMI and chlorprothixene (CPX) for two weeks were carried out. Concomitant administration of IMI and CPZ or IMI and CPX elevated the cytochrome P-450 level and accelerated IMI demethylation in in vitro study. Kinetic study of IMI demethylation carried out in the absence or in the presence of CPZ or CPX revealed that those neuroleptics inhibited IMI demethylation via competitive mechanism. Simultaneously with the enzymatic study the brain level of IMI and its demethylated metabolite desipramine (DMI) was assessed. It was found that 1 hr after withdrawal of IMI and CPZ or IMI and CPX the brain level of IMI was elevated in comparison with that of IMI treated animals, and the ratio between DMI/IMI brain concentration was decreased. When the assessment of IMI and DMI brain level was performed 24 hr after withdrawal of IMI and CPZ or IMI and CPX, there was no difference between the concentration of IMI and DMI in both, experimental and control animals.

Pharmacokinetics of morphine in striatum and nucleus accumbens: Relationship to pharmacological actions

The pharmacokinetics of morphine was compared with its ability to increase striatal dopamine turnover (estimated by an increase in DOPAC concentration) and to produce the development of a muscular rigidity (estimated as a tonic activity in the electromyogram). After systemic administration of morphine (15 mg/kg IP), the concentration of morphine in blood plasma, striatum and substantia nigra showed a parallel time course with a maximum after 30 min; in the striatum, in addition, normorphine was found in a lower concentration, but with a similar time course. The elevation of striatal DOPAC, in contrast, commenced very rapidly and lasted for about four hours. The rigidity appeared later and disappeared earlier than the striatal DOPAC elevation. After unilateral intrastriatal injection of morphine (15 micrograms), a small amount of the drug penetrated very rapidly to distant sites, such as the contralateral striatum and nucleus accumbens, as well as to the ipsilateral nucleus accumbens. The results suggest that the relationship between pharmacokinetics and pharmacodynamics of morphine, both after systemic and after local injection into the brain, is more complex than could be expected from previous findings.

Cerebral pharmacokinetics of ipsapirone in rats after different routes of administration.

Abstract— Ipsapirone, a putative non‐benzodiazepine anxiolytic, was extensively metabolized in rats to 1‐(2‐pyrimidinyl)piperazine (1‐PP) which accumulated in the brain. Neither the route of administration (i.p. or p.o.), nor prolonged administration of ipsapirone or 1‐PP affected their accumulation in the rat brain. The cytochrome P450 level and ethylmorphine N‐demethylase activity in rat liver microsomes were unchanged by chronic treatment with ipsapirone or 1‐PP. The results indicate that 1‐PP may contribute to the α2‐adrenoceptor antagonism of ipsapirone in rats and that chronic treatment with the drug does not affect its biotransformation to 1‐PP.

Different pharmacokinetic and pharmacological effects following acute and chronic treatment with imipramine

Two schedules of imipramine (IMI) administration were compared, a single intraperitoneal dose (10 mg/kg) (I) and chronic oral dosage (10 mg/kg twice a day for 14 days) (II). During schedule I, IMI reached maximal concentration in brain twice as high as that of its metabolite, desipramine (DMI), but disappeared more rapidly. During schedule II, DMI achieved concentrations twice as high as those of IMI which were maintained in a long-lasting plateau and there were considerable differences in areas of brain concentration curves. During schedule I, depletion of brain noradrenaline (NA) induced by H 77/77 and of 5-hydroxytryptamine (5-HT) by p-chloroamphetamine, were inhibited. During schedule II, after DMI concentration had become high and that of IMI low, only NA depletion but not that of 5-HT, was inhibited. At the same time, fenfluramine-induced hyperthermia was not antagonized although it was inhibited in schedule I. These findings may be relevant to those obtained clinically and may help to shed light on mechanisms of antidepressant action.

The route of administration of imipramine as a factor affecting formation of its metabolite desipramine.

ites penetrate the blood brain barrier (Baraldi 1979; Maggi & Enna 1979). However, THIP is not a substrate for GABA transaminase in vitro (Krogsgaard-Larsen et a1 1979). As our study demonstrates, after an initial redistribution THIP disappears very slowly from plasma and few metabolites accumulate in the brain (Table 2). The difference in the pharmacokinetics of THIP and muscimol may very well account for the highest efficiency and lowest toxicity of THIP when this drug is administered systemically.

A comparative study on desipramine pharmacokinetics in the rat brain after administration of desipramine or imipramine

Abstract— Chronic intraperitoneal administration of desipramine led to an extensive cumulation of the drug in brain and blood compared with that after a single dose treatment, while chronic treatment with desipramine by the oral route produced a brain concentration comparable with its level after a single oral dose. Comparison of the present results with the corresponding data of published imipramine pharmacokinetics indicated that the cumulation of desipramine in the rat brain was nearly the same when rats received desipramine or imipramine twice a day for two weeks at a dose of 10 mg kg−1 orally, or imipramine, twice a day for two weeks at a dose of 10 mg kg−1 intraperitoneally. It is suggested that these three experimental paradigms may be used as models for differentiation of the pharmacological effects of imipramine and desipramine in‐vivo.

Regional Distribution of Imipramine, Desipramine and Specific [3H]Desipramine Binding Sites in the Rat Brain after Acute and Chronic Treatment with Imipramine

Abstract— Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment of rats with imipramine has been investigated. Both substances were distributed unevenly within rat brain after single and prolonged administration of imipramine. This was partly connected with the regional cerebral blood flow, lipid content in the regions and lipophilicity of the substances investigated. It was also found that the number of specific [3H]desipramine binding sites was different in the various brain areas, and that prolonged administration of imipramine led to a decrease of their number in some of those regions. No correlation was found between the regional cerebral distribution of desipramine and the regional density of specific [3H]desipramine binding sites.

Reversal of depressant action of trazodone on avoidance behaviour by its metabolite m‐chlorophenylpiperazine

m-Chlorophenylpiperazine (CPP) is one of the metabolites of the antidepressant drug trazodone in rat (Melzacka et all979) and in man (Caccia et all981). CPP has been widely studied for its 5-hydroxytryptamine-mimetic (Maj et al 1979; Samanin et al 1979), anorectic (Samanin et al 1979, 1980) and other pharmacological properties (Maj & Lewandowska 1980; Rokosz-Pelc et al 1980; Cervo et a1 1981; Borsini et al 1981). We have found that CPP facilitates the avoidance behaviour of mice (Vetulani et al 1982), while trazodone has been reported to depress avoidance responses in rats (Silvestrini et al 1968; Gatti 1974). We have assessed in mice the effects of trazodone on avoidance behaviour and whether CPP could antagonize a possible depressant action of trazodone. In mice trazodone is metabolized to CPP (Melzacka, unpublished findings).

The effect of antidepressants on ethylmorphine and imipramine N-demethylation in rat liver microsomes.

The effects of single and multiple doses of desipramine, amitriptyline or citalopram on the rat liver microsomal cytochrome P‐450 level and on the rate of ethylmorphine and imipramine demethylation in‐vitro have been investigated. Desipramine, amitriptyline or citalopram when given to rats as a single dose, did not affect the level of cytochrome P‐450 in the liver microsomes, however, there was a tendency towards acceleration of imipramine, and particularly ethylmorphine, demethylation. Prolonged administration of desipramine and citalopram, but not amitriptyline, elevated the microsomal level of cytochrome P‐450 and accelerated the rate of ethylmorphine demethylation. All the drugs investigated, when given chronically, inhibited the rate of imipramine demethylation. Since demethylation of ethylmorphine and imipramine in a CO atmosphere was inhibited by ca 90% for the former and only by 58% for the latter, it can be assumed that prolonged administration of the drugs investigated has two different effects on the oxygenase systems in rat liver microsomes: on the one hand they stimulate the cytochrome P450 oxygenase system involved in ethylmorphine demethylation and, on the other, they inhibit the other microsomal oxygenase system involved in demethylation of imipramine.