Urinary metabolites of 10-[3′-(4″-methyl-piperazinyl)-propyl]-phenothiazine (perazine) in psychiatric patients

Summary The urinary excretion of perazine metabolites was studied in schizophrenic patients during the first weeks after initiation of perazine treatment. Quantitative determinations of 9 metabolites did not reveal important inter-individual differences in metabolite patterns. In all those patient who had not been intensively pretreated with other phenothiazines, a marked increase in the ratio of demethylation products to the corresponding N-methyl compounds was oberved between the first and fourth week of treatment. The hypothesis of an induction of a demethylating enzyme by perazine is discussed.     

Hepatic and extrahepatic metabolism of the psychotropic drugs,chlorpromazine, imipramine,and imipramine-N-oxide

Summary The metabolism of chlorpromazine (CPZ), imipramine (IP), and imipramine-N-oxide (IPNO) was studied in microsomal preparations of various rat tissues in vitro and in the isolated perfused liver. A technique for a total hepatectomy in the rat has been developed, allowing estimations of extrahepatic and hepatic drug metabolism in vivo.CPZ is converted to its sulfoxide and other metabolites in the liver and, to a minor degree, in many extrahepatic organs except brain and skin. Whole blood of several species shows a remarkable sulfoxidizing activity which can be traced to the hemoglobin and is likely to represent a heme catalysis.IP is metabolized in the liver in vitro and, to a very minor extent, in lung and kidney. Blood, brain and many other extrahepatic tissues do not metabolize this drug in vitro. However, gastro-intestinal contents of rats and humans demethylate IP to Desmethylimipramine (DMI). This is likely to be the reason for a hepatic/ extrahepatic metabolism ratio of 53/47 measured in sham operated and totally hepatectomized rats.The occurrence of IPNO metabolism in extrahepatic tissues in vitro was confirmed in vivo with hepatectomized rats. The hepatic/extrahepatic ratio is 10/90. The course of IPNO metabolism, compartmental distribution and biliary excretion of the drug and its metabolites was studied in rat liver perfusion experiments. Immediate partial conversion of IPNO to IP and DMI by hemoglobin was confirmed by perfusion experiments without the liver, and liver perfusions with hemoglobin-free perfusates.This study was supported by Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung (grants 4247 and 5258). The authors are indepted to Dr. A. R. Stofer for human autopsy material, to Mr. H. Kaufmann for the preparation of red cell fractions, and to Mr. M. Bachmann and Miss M. Lagcher for technical assistance.     

Comparison of the metabolism of the three antidepressants amitriptyline,imipramine, and chlorimipramine in vitro in rat liver microsomes

The metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), chlorimipramine (CMI) and some of their metabolites was studied in vitro in isolated liver microsomes of female Spraque-Dawley rats. Nine metabolites of AMI, seven metabolites of IMI, and 11 metabolites of CMI were quantitatively determined with high-performance liquid chromatography. The main metabolic reactions, mediated by an NADPH generating system, were hydroxylation, demethylation, and N-oxidation. The ratio of these reactions was different for the three drugs. AMI was hydroxylated more than CMI and CMI more than IMI. The order for demethylation was CMI>AMI=IMI, the order for N-oxidation IMI>CMIAMI. The substrate dependence of metabolism was investigated. Demethylation and N-oxidation increased proportionally to increasing substrate concentrations, whereas formation of hydroxylated metabolites became saturated (in the concentration range of 10^–6–10^–5 M). The in vitro metabolism was compared with the in vivo metabolism in humans, reflected by the plasma concentrations of these drugs and their metabolites. A good agreement in metabolic pathways was found.     

Forced swimming in rats: hypothermia, immobility and the effects of imipramine.

Rats when forced to swim in a restricted space not only became immobile but showed marked hypothermia. The hypothermia was greater than that observed after reserpine or Ro 4-1284 and was not antagonized by imipramine at doses which significantly reduced immobility. Hypothermia induced by forced swimming can therefore be dissociated from the immobility occurring in these conditions and also from drug-induced hypothermia.     

True and apparent side effects in a controlled trial of chlorpromazine and imipramine in depression

Five hundred and fifty-five acutely depressed patients receiving chlorpromazine and imipramine, were studied to determine the incidence and severity of drug-related side effects. The ability of clinicians to distinguish between drug-related side effects and symptoms considered natural to the depressive illnesses was also investigated. The results indicated that side effects were minimal for both active drug groups and that among the dropouts for serious side effects (31 cases) the majority were receiving chlorpromazine. Skin rash and hypotension were the most frequent reasons cited for side effect terminations from the study.It appeared that clinicians were generally able to distinguish drug-related side effects from symptoms usually associated with depression. There was some indication, however, that they tended to rate as non-medication related, certain symptoms which were actually drug-induced. The latter included muscle rigidity, edema, and dry mouth on chlorpromazine and tremulousness on imipramine.This study was supported by grants numbered MH-10445, MH-10420, MH-10546 MH-10295, MH-10331, MH-10812, MH-10330, MH-10889, MH-10495 and MH-10892 from the National Institute of Mental Health.     

Effects of chlorpromazine and imipramine on discrimination learning,consolidation, and learned behavior in two inbred strains of mice

Chlorpromazine and imipramine were administered to DBA/2J and C57BL/6J mice swimming in a Y water maze toward a light source (L Procedure, corresponding to innate tendency) or towards the dark (D Procedure, sorresponding to the acquisition of a new pattern of behavior). In two sets of experiments the drugs were administered to naive mice before and after each training session, respectively.In both strains, in the pretrial experiments, the innate tendencies were improved by both drugs; the acquisition of a new pattern of behavior was improved following imipramine but impaired following chlorpromazine. In the posttrial experiments (D procedure) the consolidation processes of both strains were improved following imipramine and impaired following chlorpromazine.In a third set of experiments imipramine was administered to previously trained mice of both strains and chlorpromazine to previously trained C57 mice. In both procedures the administration of increasing doses of both drugs was followed by a progressive lengthtening of the swimming times in the previously trained C57 mice; performance disruptions were evident in both procedures in trained DBA mice following imipramine.     

Comparative study on the inhibition of Na+, K+-activated ATPase activity by chlorpromazine,promazine, imipramine,and their monodesmethyl metabolites

Summary The inhibition of the sodium- and potassium-activated adenosine triphosphatase (Na-K-ATPase, EC 3.6.1.3) activity by chlorpromazine, promazine and imipramine was compared with that by the monodesmethyl metabolites of these drugs. The experiments were performed with a deoxycholate- and sodium iodide-treated microsomal enzyme preparation from rat brain. It was shown in dose-response curves as well as in double-reciprocal Lineweaver-Burk plots of Na-K-ATPase activity against KCl concentration that the monodesmethyl metabolites were stronger inhibitors than their parent compounds. The results obtained with the desmethyl metabolites and imipramine as inhibitors indicate competitive inhibition while the inhibition by chloropromazine and promazine was of mixed type. The experimental data appear to support the following conclusions: 1. General rules of albumin binding of drugs obviously can apply to a drug-enzyme complex. 2. The monodesmethyl metabolites of tricyclic psychoactive drugs may possess a higher affinity to receptors with protein structure.     

Uptake,subcellular distribution,and transfer processes of imipramine and its metabolites formed in rat liver perfusion systems

Summary Pharmacokinetic processes have been studied using a recirculating rat liver perfusion system. Imipramine and its major metabolites have been determined at various times up to 3 h in perfusate, liver, bile and subcellular liver fractions.Imipramine undergoes a rapid hepatic uptake, the initial extraction being close to 100%. Most of the unchanged drug is then localized in the microsomal fraction. Metabolism is not limited by uptake and follows the pathways known from previous work. Like imipramine, its lipophilic metabolite, desmethylimipramine is bound to microsomes. Its concentration ratios, endoplasmic reticulum/cytosol and liver/perfusate, are around 200. In contrast, the polar glucuronides are easily released from the ER, their site of formation, into the cytosol and presumably from there excreted into the bile. A smaller amount of the glucuronides is increted into the perfusate where they reach a steady state level. Analogous experiments with a non-recirculating perfusion system yielded comparable results except for a more rapid imipramine uptake.The results obtained in this study suggest that the pharmacokinetics of many drugs with high apparent volumes of distribution may be largely governed by intracellular binding of lipophilic compounds and translocation processes of polar metabolites.     

Effect of imipramine and desipramine on the metabolism of serotonin in midbrain raphe stimulated rats

Imipramine, 5 mg/kg, i.p., completely blocked the forebrain 5-HIAA increase in rats that have undergone midbrain raphe stimulation whereas desipramine, 5 mg/kg, i.p., did not. This finding is compatible with the hypothesis that imipramine can block selectively the membrane uptake of serotonin in the central serotoninergic neurons.     

Lysosomal trapping as an important mechanism involved in the cellular distribution of perazine and in pharmacokinetic interaction with antidepressants

Perazine, a piperazine-type phenothiazine neuroleptic, is the most frequently chosen drug for combination with antidepressants in the therapy of complex or ‘treatment-resistant’ psychiatric illnesses. The aim of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of perazine, and the pharmacokinetic interaction between the neuroleptic and antidepressants. Experiments were carried out on slices of different rat organs regarded as a system with functional lysosomes. To distinguish between lysosomal trapping and tissue binding, the experiments were performed in the absence or presence of ‘lysosomal inhibitors’, i.e. the lysosomotropic compound ammonium chloride or [H⁺] ionophore monensin, which abolish the pH-gradient of lysosomes. Under steady-state conditions, the highest tissue uptake of perazine was observed for the adipose tissue, which descended in the following order: the adipose tissue>lungs>liver>heart=brain>kidneys>muscles. The contribution of lysosomal trapping to the total tissue uptake amounted to about 40% in the liver, brain and muscles, to 30% in the kidneys, and to 25% in the heart and lungs. In the adipose tissue, no lysosomotropism of perazine was observed. Of the psychotropics studied, perazine was the only drug showing such a high degree of lysosomal trapping in muscles and distinct lysosomotropic properties in the heart. Perazine and the antidepressants used, both tricyclic (imipramine, amitriptyline) and selective serotonin reuptake inhibitors (fluoxetine, sertraline), mutually decreased their tissue uptake. The potency of imipramine to decrease perazine uptake was similar to that of the ‘lysosomal inhibitors’. Other antidepressants seemed to exert a somewhat weaker effect. The above interactions between perazine and antidepressants were not observed in the presence of ammonium chloride, which indicates that they proceeded at the level of lysosomal trapping. The adipose tissue in which the drug uptake was not affected by the ‘lysosomal inhibitors’ was not the site of such an interaction. Ammonium chloride did not affect the drug metabolism in liver slices; other tissues displayed only a negligible biotransformation of the psychotropics studied. A parallel metabolic interaction between perazine and tricyclic antidepressants took part in liver slices (i.e. perazine and antidepressants mutually inhibited their metabolic pathways), but the influence of such an interaction on the lysosomal uptake of the parent compounds in liver slices did not seem to be great. A substantial decrease in concentrations of the drugs in lysosomes (depot form) observed in vitro may lead to an increase in the concentration in vivo of the neuroleptic and antidepressants at the site of action, which, in turn, may increase the risk of cardiotoxic and anticholinergic side-effects of tricyclic antidepressants and sedative and extrapyramidal effects of the neuroleptic.     

The effects of two antidepressants,imipramine and viloxazine,upon driving performance

Forty male volunteers were randomly assigned to one of four treatment groups on a doubleblind basis: (1) Imipramine-25 mg t.d.s., (2) Viloxazine-50 mg t.d.s., (3) Placebo, and (4) Control-no tablets. Tests were carried out (1) before treatment, (2) 2 h after the first dose, (3) on Day 3 after 7 doses, and (4) on Day 7 after 21 doses. The driving tasks consisted of (1) weaving around a series of bollards while simultaneously responding to an auditory logic task and (2) a gap acceptance task. Using an analysis of covariance repeated measures design, it was found that imipramine tended to increase the level of risk acceptable to the subject as compared to either placebo or control. Imipramine also impaired performance on other tasks. Viloxazine appeared to be little different from either placebo or control on any of the tasks.     

Comparison of single dose kinetics of imipramine,nortriptyline and antipyrine in man

The single dose kinetics of imipramine (IP), nortriptyline (NT), and antipyrine (AP) were compared in 7 healthy subjects. Test doses of AP were given intravenously and test doses of IP and NT were given both orally and by intravenous infusion. The plasma concentration/time curves after intravenous IP and NT were analysed according to a 2-compartment open model. In addition a blood flow independent true clearance was calculated according to a sinusoidal perfusion model. Indirect estimates of hepatic blood flow were obtained from the oral and i.v. plasma concentration/time curves after NT administration.Compared to NT, IP had statistically significant higher clearances, shorter half-lives, and smaller apparent volumes of distribution. There was a significant correlation between apparent volume of distribution (Vd) of IP and NT (n=5,r=0.85), but only a weak correlation between the clearance measurements of the two compounds. Systemic clearance of AP and IP showed some positive correlation (n=7,r=0.73), whereas there were no significant correlations between AP and NT kinetics.The data indicate that inter- and intraindividual variations in hepatic blood flow may influence the measurements. Other possible sources of variability are individual differences in hepatic extraction kinetics, and differences in binding to blood constitutents.     

Pharmacokinetic and pharmacodynamic studies of drug interaction following oral administration of imipramine and sodium alginate in rats

Recently, the use of health foods has increased due to growing interest in health maintenance. Previous in vitro studies have shown some drugs to be adsorbed by sodium alginate, a dietary fiber, and that such adsorption was marked with tricyclic antidepressants, such as imipramine. This study investigated the pharmacokinetic and pharmacological interactions between imipramine and sodium alginate in rats. The simultaneous administration of imipramine (30 mg/kg, oral (p.o.)) and sodium alginate (3.0%, p.o.) decreased the antidepressant-like activity of imipramine in a forced swimming test. In the rats administrated imipramine and 0.3%, 1.0%, or 3.0% sodium alginate, the geometric mean ratio of the C (max) values of imipramine was 72% [90% confidence intervals (CI) = 53-91%], 64% (90% CI = 47-80%), and 58% (90% CI = 50-67%), respectively. The geometric mean ratio of the AUC(0-6) values of imipramine were 68% (90% CI = 56-80%), 74% (90% CI = 60-89%), and 87% (90% CI = 73-102%), respectively. The decrease in C (max) and AUC(0-6) was judged to be significant with a 90% CI outside the 80-125% boundaries. In addition, the T (max) value of imipramine significantly increased (P < 0.05) by coadministration with 3.0% sodium alginate. These results suggested that simultaneous administration of sodium alginate decreased the serum concentration and pharmacological action of imipramine, through a delay in its absorption. Although the clinical relevance of these findings is unclear, it is important to pay considerable attention to the interactions between imipramine and sodium alginate.     

Effects of chlordiazepoxide,amitriptyline, imipramine,and their combinations on avoidance behaviour in mice

Chlordiazepoxide, imipramine, and amitriptyline, given alone or in combination, were tested in mice subjected to 5 daily 100-trial avoidance sessions in the shuttle-box. When the drugs were given alone, chlordiazepoxide and the lower doses of imipramine facilitated avoidance behaviour. The higher doses of the two antidepressants impaired avoidance behaviour. Mixtures of chlordiazepoxide and imipramine produced some facilitating effects, while depressant effects prevailed in the chlordiazepoxide-amitriptyline combinations.     

Differential effects of ethanol and other inducers of drug metabolism on the two forms of hamster liver microsomal aniline hydroxylase

The aniline hydroxylase activity of microsomes isolated from hamster liver can be differentiated kinetically into high affinity (low K_m, form I) and low affinity (high K_m, form II) forms. Microsomes isolated from uninduced animals contain slightly more form I activity. The activity of the low affinity form (form II) is preferentially enhanced by Aroclor or 3-methylcholanthrene treatment, while phenobarbital treatment increases the activity of both forms. Chronic ethanol consumption results in enhancement of only the high affinity form (form I).     

Hepta-, hexa-, tetra- and dichloronaphthalene congeners as inducers of hepatic microsomal drug-metabolizing enzymes

Pretreatment of immature male Wistar rats with 1,2,3,4,5,6,7-hepta-, 1,2,3,4,5,6,8-hepta- and 1,2,3,4,5,6-hexachloronaphthalene resulted in the induction of several hepatic microsomal drug-metabolizing enzymes. The enzymic activities, reduced cytochrome P-450:CO and ethylisocyanide binding difference spectra and electrophoretic mobilities of the induced microsomal proteins were comparable to those observed after administration of the classical inducer of microsomal aryl hydrocarbon hydroxylase, 3-methylcholanthrene. The 1,2,3,4,5,6,7-heptachloronaphthalene congener, which is fully substituted in the lateral 2,3,6 and 7 positions, was more potent than the 1,2,3,4,5,6,8-hepta- and the 1,2,3,4,5,6-hexachloronaphthalene congeners which contain only 3 lateral chloro substituents. 1,2,3,4-Tetra- and several lower chlorinated naphthalenes were inactive as inducers of microsomal aryl hydrocarbon hydroxylase. The effects of structure on the induction activities of the polychlorinated naphthalenes were similar to those observed for other halogenated aryl hydrocarbons.     

The demethylation of imipramine and clomipramine as apparent from their plasma kinetics

The demetylation of imipramine and clomipramine was studied after administration by different routes of single doses of clomipramine hydrochloride and multiple doses of clomipramine as well as imipramine hydrochloride.Five healthy volunteers received 1 mg of clomipramine hydrochloride/kg body weight as single oral and intramuscular doses on different occasions for the purpose of studying the plasma levels of clomipramine and the desmethylclomipramine formed. Desmethyl-clomipramine was found in the plasma in four of the subjects after oral intake but only in one subject after intramuscular injection. The peak levles of clomipramine were considerably higher after intramuscular than after oral administration. The half-lives of clomipramine after oral administration ranged from 11.6–35.8 h and after intramuscular administration from 20.1–39.6 h .Twenty subjects received either imipramine or clomipramine both orally and intramuscularly during a period of 3 weeks in a crossover design. The plasma levels of imipramine and clomipramine and their demethylated metabolites desipramine and desmethyl-clomipramine were determined during the treatment. The ratio between the plasma level of the parent drug and its demethylated metabolite was on average twice as high during intramuscular as during oral treatment.     

The action of imipramine,amitriptyline, doxepin and butriptyline in an operant conditioning schedule

The behavioural action of imipramine, amitriptyline, doxepin and butriptyline was studied in an operant conditioning programme composed of two concurrent schedules, one food reinforced and the other an avoidance schedule. The possibility that the position (near or far from the food tray) of the two levers in the cage may affect drug behavioural action was investigated.Tricyclic antidepressants caused a dose dependent depression of the food reinforced responses; the avoidance reflex was slightly depressed at the highest doses only. This pattern of antidepressive activity was compared with the patterns obtained in the same test with other CNS agents.     

The effects of amphetamine,imipramine and ICI 58,834 (Vivalan), a potential antidepressant,on unconditioned behaviour in rats

The effects of amphetamine, imipramine and ICI 58,834 (Vivalan**), on the unconditioned behaviour of rats were compared using a novelty preference test and the open field test. Overall, the effects of ICI 58,834 (Vivalan**) showed a marked resemblance to those of imipramine but differed from those of amphetamine. It is suggested that an adequate explanation of these drugs' effects can be offered in terms of changes in emotional reactivity, in general activity, and in exploratory activity. A dissociation of drug effects on general and exploratory activity in the novelty preference test was demonstrated. The use of this test and the open field test in drug screening is briefly discussed.This research was supported by a grant from Imperial Chemical Industries Ltd., Pharmaceuticals Division, Alderley Park, Macclesfield, England.Trade-mark, the property of Imperial Chemical Industries Ltd.