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PubMed2005

Inhibition of rat liver CYP2D in vitro and after 1-day and long-term exposure to neuroleptics in vivo-possible involvement of different mechanisms.

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2D measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally (i.p.) for 1-day or 2-weeks (twice a day) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine, perazine 10 mg kg(-1); chlorpromazine 3 mg kg(-1); haloperidol 0.3 mg kg(-1); risperidone 0.1 mg kg(-1); sertindole 0.05 mg kg(-1)), in the absence of the neuroleptics in vitro. Neuroleptics added in vitro to control liver microsomes decreased the activity of the rat CYP2D by competitive or mixed inhibition of the enzyme. Thioridazine (Ki=15 microM) was the most potent inhibitor of the rat CYP2D among the drugs studied, whose effect was more pronounced than that of the other neuroleptics tested: phenothiazines (Ki=18-23 microM), haloperidol (Ki=32 microM), sertindole (Ki=51 microM) or risperidone (Ki=165 microM). The investigated neuroleptics-when given to rats in vivo-also seemed to exert an inhibitory effect on CYP2D via other mechanisms. One-day exposure of rats to the classic neuroleptics decreased the activity of CYP2D in rat liver microsomes. After chronic treatment with the investigated neuroleptics, the decreased CYP2D activity produced by the phenothiazines was still maintained, while that caused by haloperidol diminished. Moreover, risperidone decreased the activity of that enzyme. The obtained results indicate drug- and time-dependent interactions between the investigated neuroleptics and the CYP2D subfamily of rat cytochrome P-450, which may proceed via different mechanisms: (1) competitive or mixed inhibition of CYP2D shown in vitro, the inhibitory effects of phenothiazines being stronger than those of haloperidol or atypical neuroleptics, but weaker than the effects of the respective drugs on human CYP2D6; (2) in vivo inhibition of CYP2D, produced by both 1-day and chronic treatment with phenothiazines, which suggests inactivation of enzyme by intermediate metabolites; (3) in vivo inhibition of CYP2D by risperidone, produced only by chronic treatment with the drug, which suggests its influence on the enzyme regulation.

Animals↗
PubMed1997

Antipsychotic drug effects on glutamatergic activity.

Previous work from this laboratory indicated that some antipsychotic drugs possess unique action at N-methyl-D-aspartate (NMDA) receptors. A functional neurochemical assay showed that, at concentrations similar to those found in the cerebrospinal fluid (CSF) of schizophrenics, antipsychotic drugs augment NMDA activity while, at higher concentrations, NMDA activity is suppressed. Using similar analysis, the present paper reports that this pattern of response is also shown by the antipsychotic drugs thioridazine and chlorpromazine. In contrast, promazine, which is structurally similar to chlorpromazine but lacking both D2-effects and antipsychotic potency, had no influence on NMDA receptors. In addition, sulpiride and metoclopramide, drugs with high affinity for D2-dopamine receptors but with weak or no antipsychotic efficacy, also lack effects at the NMDA receptor. Thus, the drugs with clinical efficacy that were tested in the present and previous studies all share unique influence on NMDA receptors. Further work with other antipsychotic agents will be necessary to determine if influence on NMDA receptors contributes to antipsychotic effectiveness.

Animals↗
PubMed1977

A gas-liquid chromatographic method for the determination of butriptyline in serum.

1. A gas-liquid chromatographic (GC) method for the analysis of butriptyline in serum has been development. Quantitation is based on the peak height ratio between butriptyline and promazine used as internal standard. A triple partition provides a "clean" extract. A detection limit of 10 ng/ml is achieved. 2. The usefulness of the method has been demonstrated in bioavailability studies in dogs.

Animals↗
PubMed1999

Pharmacological profile of neuroleptics at human monoamine transporters.

Using radioligand binding techniques, we determined the equilibrium dissociation constants (K(D)) for 37 neuroleptics and one metabolite of a neuroleptic (haloperidol metabolite) for the human serotonin, norepinephrine, and dopamine transporters with [3H]imipramine, [3H]nisoxetine, and [3H]WIN35428, respectively. Among neuroleptics, the four most potent compounds at the human serotonin transporter were triflupromazine, fluperlapine, chlorpromazine, and ziprasidone (K(D) 24-39 nM); and at the norepinephrine transporter, chlorpromazine, zotepine, chlorprothixene, and promazine (K(D) 19-25 nM). At the human dopamine transporter, only pimozide (K(D) = 69+/-3) ziprasidone (K(D) = 76+/-5) had notable potency. These data may be useful in predicting therapeutic and adverse effects, including drug interactions of neuroleptics.

Antipsychotic Agents↗
PubMed2003

An evaluation of protein assays for quantitative determination of drugs.

We have evaluated the response of six protein assays [the biuret, Lowry, bicinchoninic acid (BCA), Coomassie Brilliant Blue (CBB), Pyrogallol Red-Molybdate (PRM), and benzethonium chloride (BEC)] to 21 pharmaceutical drugs. The drugs evaluated were analgesics (acetaminophen, aspirin, codeine, methadone, morphine and pethidine), antibiotics (amoxicillin, ampicillin, gentamicin, neomycin, penicillin G and vancomycin), antipsychotics (chlorpromazine, fluphenazine, prochlorperazine, promazine and thioridazine) and water-soluble vitamins (ascorbic acid, niacinamide, pantothenic acid and pyridoxine). The biuret, Lowry and BCA assays responded strongly to most of the drugs tested. The PRM assay gave a sensitive response to the aminoglycoside antibiotics (gentamicin and neomycin) and the antipsychotic drugs. In contrast, the CBB assay showed little response to the aminoglycosides and gave a relatively poor response with the antipsychotics. The BEC assay did not respond significantly to the drugs tested. The response of the protein assays to the drugs was further evaluated by investigating the linearity of the response and the combined response of drug plus protein. The results are discussed with reference to drug interference in protein assays and the development of new methods for the quantification of drugs in protein-free solution.

Analgesics↗
PubMed2003

Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions.

Distribution of a drug in the body is dependent on its permeation properties, the blood flow rates in various tissues, and on plasma and tissue uptake. The distribution of drugs in vivo is largely determined by uptake competitions between blood and tissues, as well as competitions among individual tissues. Basic lipophilic drugs are characterized by extensive accumulation in tissues, which leads to a high volume of distribution. Nonspecific binding to cellular membranes and uptake by acidic compartments (mainly lysosomes) are responsible for such a distribution pattern. Lysosomal trapping is an important mechanism of distribution of basic psychotropic drugs; however, the tissue distribution of the aliphatic-type phenothiazine neuroleptic promazine, tricyclic antidepressants (TADs) and selective serotonin reuptake inhibitors (SSRIs) depends more on phospholipid binding than on lysosomal trapping, whereas in the case thioridazine and perazine, lysosomal trapping is as important for the tissue uptake as is phospholipid binding. Neuroleptics and antidepressants mutually inhibit their lysosomal uptake. A decrease in the intralysosomal drug concentrations in vivo leads to a shift of the drug from organs abundant in lysosomes (lungs, liver and kidneys) to those poor in these organella, e.g., the heart, which may be of clinical importance (cardiotoxicity). The brain is not a homogenous organ, i.e., the phospholipid pattern and density of lysosomes vary in its different regions. Therefore, the contribution of the two mechanisms (lysosomal trapping and tissue binding) to total drug uptake is different in areas of the brain. Both lysosomal trapping and binding to cellular elements for psychotropics are higher in the grey matter and neurons than in the white matter and astrocytes, respectively. Lysosomal trapping and distribution interactions of psychotropics take place mainly in neurons. A decrease (via a distributive interaction) in the concentration of psychotropics in lysosomes (depot) may lead to an increase in their level in membranes and tissue fluids (i.e., in concentrations and compartments relevant to their pharmacological action) and, in consequence, to enhancement of the drug binding to neurotransmitter receptors and/or transporters.

Antidepressive Agents↗
PubMed2000

Comparative in vitro activity of phenothiazines against multidrug-resistant Mycobacterium tuberculosis.

The comparative activity of five phenothiazines against multidrug-resistant strains of Mycobacterium tuberculosis (MDRTB) was studied using the Bactec 460 system. The order of antimycobacterial activity of the phenothiazines was: chlorpromazine = thioridazine > promethazine > promazine = desipramine. However, the levels required for an MIC 50 exceeded 1 mg/l and are beyond those that are clinically achievable. As phenothiazines are concentrated by macrophages that phagocytose and have in situ activity against mycobacteria, these agents may be considered for use as adjuvants for the management of freshly diagnosed tuberculosis in patients from populations with a high prevalence of MDRTB.

Antitubercular Agents↗
PubMed1979

Electrochemical oxidation of hydroxylated phenothiazine and imipramine derivatives.

The electrochemical oxidations of several hydroxylated derivatives of promazine, chlorpromazine, imipramine, and 3-chloroimipramine are examined and compared. Oxidation of the monohydroxyphenothiazine derivatives leads to both dihydroxy species and substituted benzoquinones, while oxidation of hydroxylated imipramines leads to only the corresponding benzoquinones. The oxidation potentials of 17 tricyclic psychoactive drugs and metabolites are tabulated and compared. The potential importance of these results to drug activity and side effects is discussed.

Electrochemistry↗
PubMed1979

Effect of structure on phenothiazine cation radical reactions in aqueous buffers.

The reactions of the cation radicals of 11 phenothiazine tranquilizers were examined in mildly acidic aqueous buffers. Of the 11, those having an aminopropyl side chain in the 10 position reacted to form 0.5 mol of sulfoxide and 0.5 mol of parent drug per mole of initial radical. Cation radicals with different side chains react to form additional products, which remain to be identified but probably result from hydroxylation of the phenothiazine ring. The decay kinetics of three of the cation radicals undergoing reactions with known stoichiometry, namely, chloropromazine, promazine, and triflupromazine, were studied in detail, and it was concluded that they all react via the same mechanism. The mechanism involves attack of the cation radical by a nucleophile, and radicals with electron-withdrawing groups in the 2 position react more quickly. Since the cation radicals with faster reaction rates with nucleophiles are more pharmacologically active, it is hypothesized that the cation radical-nucleophile interaction may be responsible for binding of phenothiazines to receptor proteins.

Antipsychotic Agents↗
PubMed2003

Solubilization of cationic drugs in lung surfactant.

PURPOSE: The association of hydrophobic, cationic drugs with lung surfactant was determined to assess the pharmacokinetic implications on drug disposition and retention in the lung. METHODS: The distribution coefficients, K, were determined at 25 and 37 degrees in normal saline solution buffered at pH 7.4 for a series of structurally related, cationic drugs. Drugs were dispersed into lung surfactant, equilibrated, and then centrifuged to separate the aqueous phase from the surfactant pellet. Drug concentrations in the supernatant and pellet were determined following dilution using spectrophotometric assays. In addition, the apparent acid dissociation constant of quinacrine in the presence and absence of surfactant was determined by measuring the pH-dependent absorption spectra. The effect of stereochemistry on the distribution of drugs into surfactant was examined with (R)- and (S)-propranolol. RESULTS: The mole fraction distribution coefficients for amitriptyline, promethazine, promazine, ethopropazine, imipramine, R-propranolol, and S-propranolol at 25 degrees C were 6,560 +/- 500, 28,400 +/- 1,500, 12,100 +/- 840, 5,480 +/- 330, 4,490 +/- 250, 8,680 +/- 260, 8,190 +/- 530, respectively. At 37 degrees C, the distribution coefficients were generally smaller indicating a significant exothermic heat of transfer for these solutes from aqueous solution to the lung surfactant. The pKa of quinacrine was 7.43 +/- 0.04 in aqueous solution and was shifted to 7.62 +/- 0.06 in the presence of lung surfactant. From this shift, the double layer potential for quinacrine-lung surfactant was estimated to be -0.012 V assuming a dielectric constant equivalent to that of water. CONCLUSIONS: Cationic drugs have very favorable distributions from an aqueous solution to the lipid phase of lung surfactant. The transfer process generally has both a large entropic and enthalpic contribution. The latter thermodynamic aspect may be related to the charge interaction between the solute and the negatively charged surfactant. Finally, no significant effect of stereochemistry was evident with the distribution of (R)- and (S)-propranolol.

Cations↗
PubMed2000

Human term placental lipoxygenase-mediated N-demethylation of phenothiazines and insecticides in the presence of linoleic acid.

This study investigated the hypothesis that human term placental lipoxygenase (HTPLO) and soybean lipoxygenase (SLO) are capable of mediating N-demethylation of selected phenothiazines and insecticides in the presence of linoleic acid (LA). In addition to being LA dependent, the N-demethylation reaction mediated by HTPLO and SLO was limited by incubation time, pH of the medium, concentration of the enzyme and the substrate. Using Nash reagent to monitor formaldehyde production, the specific activity for LA-dependent N-demethylation of chlorpromazine, a model phenothiazine, was determined to be 1.7+/-0.3 nmoles/min/mg HTPLO. Besides chlorpromazine, N-demethylation of promazine, promethazine and trimeprazine was also observed. The insecticide, aminocarb, displayed a specific activity of 2.2+/-0.3 nmoles/min/mg HTPLO for N-demethylation. Other insecticides, namely chlordimeform, dicrotophos and zectran, were oxidized in a similar manner. As compared with HTPLO, the rates of N-demethylation of phenothiazines and insecticides mediated by SLO were higher. Classical inhibitors of lipoxygenase, as well as antioxidants and free radical scavengers, caused a dose-dependent reduction in the production of formaldehyde from chlorpromazine and aminocarb by HTPLO. These results clearly demonstrate the ability of polyunsaturated free fatty acids to support N-demethylation of xenobiotics via the lipoxygenase pathway.

Carbamates↗
PubMed1991

Misuse of zopiclone and convulsions during withdrawal.

It has been documented that benzodiazepines have the potential to cause dependence and withdrawal reactions, including convulsions. However, the available data concerning zopiclone, a nonbenzodiazepine hypnotic, are insufficient. The present study describes the case of a 36-year-old man who repeatedly misused zopiclone, in daily doses of 60-90 mg. Furthermore, the patient suffered from convulsion on two occasions following abrupt withdrawal of zopiclone. The concomitant use of alcohol, trimipramine, and promazine may have contributed to the development of convulsions. It is concluded that zopiclone may cause problems associated with misuse and withdrawal reactions similar to those of benzodiazepines.

Adult↗
PubMed1991

Characterization of lipid domains in erythrocyte membranes.

Fluorescence digital imaging microscopy was used to study the lateral distribution of the lipid components in erythrocyte membranes. Intact erythrocytes labeled with phospholipids containing a fluorophore attached to one fatty acid chain showed an uneven distribution of the phospholipids in the membrane thereby demonstrating the presence of membrane domains. The enrichment of the lipotropic compound chlor-promazine in domains in intact erythrocytes also suggested that the domains are lipid-enriched regions. Similar membrane domains were present in erythrocyte ghosts. The phospholipid enrichment was increased in the domains by inducing membrane protein aggregation. Double-labeling experiments were done to determine the relative distributions of different phospholipids in the membrane. Vesicles made from extracted lipids did not show the presence of domains consistent with the conclusion that membrane proteins were responsible for creating the domains. Overall, it was found that large domains exist in the red blood cell membrane with unequal enrichment of the different phospholipid species.

4-Chloro-7-nitrobenzofurazan↗
PubMed2001

Trypanosoma cruzi trypanothione reductase is inactivated by peroxidase-generated phenothiazine cationic radicals.

Trypanosoma cruzi trypanothione reductase (TR) was irreversibly inhibited by peroxidase/H2O2 /phenothiazine (PTZ) systems. TR inactivation depended on (a) time of incubation with the phenothiazine system; (b) the peroxidase nature and (c) the PTZ structure and concentration. With the most effective systems, TR inactivation kinetics were biphasic, with a relatively fast initial phase during which about 75% of the enzyme activity was lost, followed by a slower phase leading to total enzyme inactivation. GSH prevented TR inactivation by the peroxidase/H2O2/PTZ+* systems. Production of PTZ+* cation radicals by PTZ peroxidation was essential for TR inactivation. Horseradish peroxidase, leukocyte myeloperoxidase (MPO) and the pseudo-peroxidase myoglobin (Mb) were effective catalysts of PTZ+* production. Promazine, thioridazine, chlorpromazine, propionylpromazine prochlorperazine, perphenazine and trimeprazine were effective constituents of the HRP/H2O2 /PTZ system. The presence of substituents at the PTZ nucleus position 2 exerted significant influence on PTZ activity, as shown by the different effects of 2-trifluoromethyl and 2-H or 2-chlorophenothiazines. The PTZ+* cation radicals disproportionation regenerated the non-radical PTZ molecule and produced the PTZ sulfoxide that was inactive on TR. Thiol compounds including GSH interacted with PTZ+* cation radicals transferring an electron from the sulfide anion to the PTZ+*, thus nullifying the PTZ+* biological and chemical activities.

Animals↗
PubMed1999

Noncompetitive, Ca(2+)-independent inhibition of pyruvate dehydrogenase phosphatase by fluphenazine.

The effects of two different classes of calmodulin antagonists on the catalytic activities of purified pyruvate dehydrogenase (PDH) phosphatase and PDH complex (PDC) were studied. In general, PDH phosphatase was more strongly inhibited than PDC by the calmodulin antagonists with the following potency order: fluphenazine > chlorpromazine > thioridazine > triflupromazine. Promazine and two sulfonamides (W-5 and W-7) did not suppress PDH phosphatase activity at 1 mM concentrations, while about 20% of PDC activity was inhibited by these antagonists. Fluphenazine-mediated inhibition of PDH phosphatase was observed with the purified PDC as well as intact mitochondria. Although Ca2+ stimulates PDH phosphatase activity, the addition of exogenous Ca2+ did not overcome the inhibition by calmodulin antagonists. These results suggest that the suppression of PDH phosphatase activity is dependent upon the structure of the individual calmodulin antagonist and appears to be Ca(2+)-independent. Kinetic analysis showed a noncompetitive inhibition of PDH phosphatase by fluphenazine, indicating that it binds to different site(s) from the catalytic site of the enzyme.

Animals↗
PubMedDate not supplied

Study of the metabolism of phenothiazines: determination of N-demethylated phenothiazines in urine.

When phenothiazine drugs (chlorpromazine, promazine, promethazine, propiomazine, propionylpromazine, trifluoperazine and trimeprazine) were reacted with m-chloroperbenzoic acid, N-demethylated phenothiazines were obtained in moderate yield. The mass spectra of the N-demethylated phenothiazines showed either m/z 44 and 72 or m/z 58 as characteristic ions depending on their side chain. The N-demethylated propiomazine was identified as a metabolite of propiomazine from the urine of a rat which was given propiomazine orally.

Animals↗
PubMed1983

Liquid chromatographic separation of antidepressant drugs: II. Amoxapine and maprotiline.

The simultaneous serum analysis of amoxapine (AMOX) and its major metabolite 8-hydroxyamoxapine (8-OH AMOX), and maprotiline (MAP) and its major metabolite desmethylmaprotiline (D-MAP) by high-performance liquid chromatography (HPLC) and ultraviolet detection is described here. AMOX and 8-OH AMOX were detected at 254 nm at 0.01 absorbance units full scale (AUFS). MAP and D-MAP were detected at 214 nm at 0.05 AUFS. Serum (1.0 ml collected in plastic) extraction was by Bond-Elut C18 columns. The compounds of interest were eluted from the columns with 10 mM methanolic ammonium acetate. The eluates are evaporated at 56-58 degrees C and reconstituted with 200 microliter of mobile phase. The mobile phase was absolute ethanol-acetonitrile-tert-butylamine (98:2:0.05, vol/vol), and the flow rate was 2.0 ml/min. Absolute recoveries range from 97 to 100% for all compounds. HPLC was done on a 5-micron (4.6 X 250 mm) silica-packing column (normal phase). Separations on a 10-micron silica column (3.9 X 300 mm) are also discussed. Peak height ratios using trimipramine as the internal standard were linear for each drug between 25 and 1080 ng/ml. AMOX and 8-OH AMOX ratios with promazine as the internal standard were linear between 25 and 1080 ng/ml. Detection limits were 3 ng/ml for AMOX and 8-OH AMOX, 12 ng/ml for D-MAP, and 15 ng/ml for MAP. Coefficients of within-day and day-to-day variation at three concentration levels were less than 10.8% and 10.5%, respectively, for all compounds. Correlations of AMOX, 8-OH AMOX, and MAP sample assays using gas chromatography (or gas chromatography-mass spectrometry) and this method were compared. Steady-state daily dosages and corresponding serum levels are presented for seven patients. AMOX and 8-OH AMOX concentrations for 37 patients are given; these show that the ratios of these compounds are highly variable between patients. MAP and D-MAP concentrations for 30 patients show that D-MAP can be a significant fraction of the circulating drug. Assay time for 8-OH AMOX/AMOX was 6.5 min and less than 13 min for D-MAP/MAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxapine↗
PubMed2005

Application notes on the use of softer X-rays for anomalous powder diffraction.

An in-vacuum diffractometer has been modified to collect powder diffraction data from a sample of promazine hydrochloride. Strong anomalous contrast has been observed at, or close to, the sulphur edge. Based on the data collected, a bespoke diffractometer has been designed that, together with minor changes to the geometry of the experiment, will enable the routine collection of powder data at absorption edges below 5.5 keV.

Equipment Design↗