RESUMO
Antipsychotics are often used in combination with other psychotropic drugs to treat a variety of psychiatric disorders, as well as in combination with other drugs taken by patients with co-morbidities. When these drugs are combined, the potential for drug-drug interaction increases, leading to side-effects, in addition to the predicted increase in effectiveness. The present study aimed at examining the effects of the three atypical neuroleptics asenapine, lurasidone and iloperidone on cytochrome P450 (CYP) expression in the human liver. The study was carried out on cryopreserved human hepatocytes. The hepatotoxicity of the tested drugs was assessed after exposure to the neuroleptics (LDH cytotoxicity assay). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6ß-hydroxylation (CYP3A4). Parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Asenapine significantly decreased the mRNA level and activity of CYP1A2, while iloperidone potently diminished the mRNA level and activity of CYP3A4 in the cultures of human hepatocytes. Lurasidone did not affect the expression and activity of any of the investigated human CYP enzymes. The presented findings may have clinical implications for the prediction of potential drug-drug interactions involving the asenapine-induced inhibition of metabolism of CYP1A2 substrates (e.g. caffeine, theophylline, melatonin, tricyclic antidepressants, phenacetin, propranolol) and iloperidone-induced inhibition of CYP3A4 substrates (e.g. antidepressants, benzodiazepines, atorvastatin, macrolide antibiotics, calcium channel antagonists).
Assuntos
Antipsicóticos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Hepatócitos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoxazóis/farmacologia , Cloridrato de Lurasidona/farmacologia , Piperidinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Dibenzocicloeptenos , Interações Medicamentosas , Hepatócitos/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , RNA Mensageiro/metabolismoRESUMO
Our recent work suggested a negative effect for the serotonergic innervation of the paraventricular nuclei (PVN) of the hypothalamus on growth hormone secretion and growth hormone-dependent expression of CYP2C11. The aim of our present research was to determine the effect of the activation of the 5-hydroxytryptamine [(5-HT) serotonin] 5-HT1 or 5-HT2 receptors in the PVN on the expression and activity of cytochrome P450 in male rat liver. The serotonergic agonists 5-carboxyamidotryptamine [(5-CT), a 5-HT1 receptor-type agonist], 8-hydroxy-2-(di-n-propyloamino)-tetralin [(8-OH-DPAT), a 5-HT1A receptor agonist], sumatriptan (a 5-HT1B/D receptor agonist), and 2,5-dimethoxy-4-iodoamphetamine [(DOI), a 5-HT2A/C receptor agonist] were individually injected into the PVN. The liver cytochrome P450 activity and expression and the levels of serum and pituitary and hypothalamic hormones were measured. 5-CT and 8-OH-DPAT significantly decreased the activity and expression of CYP2C11 at both the mRNA and protein levels, which was accompanied by an increase in pituitary and hypothalamic somatostatin levels and a decrease in the serum growth hormone concentration. The expression of CYP3A1/23 also decreased. The serum corticosterone concentration declined after the injection of 8-OH-DPAT. The obtained results indicated that 5-HT1A but not the 5-HT1B/D or 5-HT2 receptors in the PVN are engaged in the negative neuroendocrine regulation of cytochrome P450 via the stimulation of hypothalamic somatostatin secretion and in the decreases in the serum growth hormone and corticosterone concentrations. Since the affected enzymes metabolize steroids and drugs and 5-HT1A receptors are engaged in the action of psychotropic drugs, the results obtained may be of both physiologic and pharmacological meaning.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Família 2 do Citocromo P450/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Esteroide 16-alfa-Hidroxilase/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Corticosterona/metabolismo , Hormônio do Crescimento/metabolismo , Fígado , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Wistar , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Melatonin is used in the therapy of sleep and mood disorders and as a neuroprotective agent. The aim of our study was to demonstrate that melatonin supported (via its deacetylation to 5-methoxytryptamine) CYP2D-mediated synthesis of serotonin from 5-methoxytryptamine. We measured serotonin tissue content in some brain regions (the cortex, hippocampus, nucleus accumbens, striatum, thalamus, hypothalamus, brain stem, medulla oblongata, and cerebellum) (model A), as well as its extracellular concentration in the striatum using an in vivo microdialysis (model B) after melatonin injection (100 mg/kg i.p.) to male Wistar rats. Melatonin increased the tissue concentration of serotonin in the brain structures studied of naïve, sham-operated, or serotonergic neurotoxin (5,7-dihydroxytryptamine)-lesioned rats (model A). Intracerebroventricular quinine (a CYP2D inhibitor) prevented the melatonin-induced increase in serotonin concentration. In the presence of pargyline (a monoaminoxidase inhibitor), the effect of melatonin was not visible in the majority of the brain structures studied but could be seen in all of them in 5,7-dihydroxytryptamine-lesioned animals when serotonin storage and synthesis via a classic tryptophan pathway was diminished. Melatonin alone did not significantly increase extracellular serotonin concentration in the striatum of naïve rats but raised its content in pargyline-pretreated animals (model B). The CYP2D inhibitor propafenone given intrastructurally prevented the melatonin-induced increase in striatal serotonin in those animals. The obtained results indicate that melatonin supports CYP2D-catalyzed serotonin synthesis from 5-methoxytryptamine in the brain in vivo, which closes the serotonin-melatonin-serotonin biochemical cycle. The metabolism of exogenous melatonin to the neurotransmitter serotonin may be regarded as a newly recognized additional component of its pharmacological action.
Assuntos
Encéfalo/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Melatonina/metabolismo , Serotonina/metabolismo , 5-Metoxitriptamina/metabolismo , Animais , Masculino , Microdiálise/métodos , Neurotransmissores/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: T-cell tolerance of allergic cutaneous contact sensitivity (CS) induced in mice by high doses of reactive hapten is mediated by suppressor cells that release antigen-specific suppressive nanovesicles. OBJECTIVE: We sought to determine the mechanism or mechanisms of immune suppression mediated by the nanovesicles. METHODS: T-cell tolerance was induced by means of intravenous injection of hapten conjugated to self-antigens of syngeneic erythrocytes and subsequent contact immunization with the same hapten. Lymph node and spleen cells from tolerized or control donors were harvested and cultured to produce a supernatant containing suppressive nanovesicles that were isolated from the tolerized mice for testing in active and adoptive cell-transfer models of CS. RESULTS: Tolerance was shown due to exosome-like nanovesicles in the supernatants of CD8(+) suppressor T cells that were not regulatory T cells. Antigen specificity of the suppressive nanovesicles was conferred by a surface coat of antibody light chains or possibly whole antibody, allowing targeted delivery of selected inhibitory microRNA (miRNA)-150 to CS effector T cells. Nanovesicles also inhibited CS in actively sensitized mice after systemic injection at the peak of the responses. The role of antibody and miRNA-150 was established by tolerizing either panimmunoglobulin-deficient JH(-/-) or miRNA-150(-/-) mice that produced nonsuppressive nanovesicles. These nanovesicles could be made suppressive by adding antigen-specific antibody light chains or miRNA-150, respectively. CONCLUSIONS: This is the first example of T-cell regulation through systemic transit of exosome-like nanovesicles delivering a chosen inhibitory miRNA to target effector T cells in an antigen-specific manner by a surface coating of antibody light chains.
Assuntos
Anticorpos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dermatite de Contato/prevenção & controle , Epitopos , Exossomos/fisiologia , Tolerância Imunológica , MicroRNAs/fisiologia , Animais , Humanos , Camundongos , Biossíntese de Proteínas , Linfócitos T Reguladores/imunologiaRESUMO
Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo.
Assuntos
Encéfalo/metabolismo , Serotonina/biossíntese , 5-Metoxitriptamina/metabolismo , Animais , Catálise , Sistema Enzimático do Citocromo P-450 , Humanos , Masculino , Microssomos/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Our earlier studies have shown that the brain noradrenergic system regulates cytochrome P450 (CYP) in rat liver via neuroendocrine mechanism. In the present work, a comparative study on the effect of intraperitoneal administration of the noradrenergic neurotoxin DSP-4 and the knockout of noradrenaline transporter (NET-KO) on the CYP3A in the liver of male and female mice was performed. METHODS: The experiments were conducted on C57BL/6J WT and NET-/- male/female mice. DSP-4 was injected intraperitoneally as a single dose (50 mg/kg ip.) to WT mice. The activity of CYP3A was measured as the rate of 6ß-hydroxylation of testosterone in liver microsomes. The CYP3A protein level was estimated by Western blotting. RESULTS: DSP-4 evoked a selective decrease in the noradrenaline level in the brain of male and female mice. At the same time, DSP-4 reduced the CYP3A activity in males, but not in females. The level of CYP3A protein was not changed. The NET knockout did not affect the CYP3A activity/protein in both sexes. CONCLUSIONS: The results with DSP-4 treated mice showed sex-dependent differences in the regulation of liver CYP3A by the brain noradrenergic system (with only males being responsive), and revealed that the NET knockout did not affect CYP3A in both sexes. Further studies into the hypothalamic-pituitary-gonadal hormones in DSP-4 treated mice may explain sex-specific differences in CYP3A regulation, whereas investigation of monoaminergic receptor sensitivity in the hypothalamic/pituitary areas of NET-/- mice will allow for understanding a lack of changes in the CYP3A activity in the NET-KO animals.
Assuntos
Citocromo P-450 CYP3A , Neurotoxinas , Ratos , Animais , Camundongos , Feminino , Masculino , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Neurotoxinas/metabolismo , Neurotoxinas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/metabolismo , Fígado , Testosterona/metabolismoRESUMO
BACKGROUND: Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs. METHODS: The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6ß-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. RESULTS: The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. CONCLUSION: Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.
Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Citocromo P-450 CYP3A/biossíntese , Indução Enzimática/efeitos dos fármacos , Metotrimeprazina/farmacologia , Células Cultivadas , Inibidores das Enzimas do Citocromo P-450 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado , RNA Mensageiro/biossínteseRESUMO
BACKGROUND: The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). METHODS: The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4'-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1'-hydroxylation/CYP2D6 and testosterone 6ß-hydroxylation/CYP3A4, respectively, using HPLC. RESULTS: Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (Ki = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (Ki = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (Ki = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (Ki = 37.5 and 85 µM in microsomes and supersomes). CONCLUSION: The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Isoxazóis/farmacologia , Cloridrato de Lurasidona/farmacologia , Piperidinas/farmacologia , Animais , Antipsicóticos/farmacologia , Baculoviridae/genética , Sistema Enzimático do Citocromo P-450/metabolismo , DNA Complementar/genética , Humanos , Insetos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologiaRESUMO
BACKGROUND: Inhibition of cytochrome P450 (CYP) enzymes is the most common cause of harmful drug-drug interactions. The present study aimed at examining the inhibitory effect of the novel antipsychotic drug asenapine on the main CYP enzymes in human liver. METHODS: The experiments were performed in vitro using pooled human liver microsomes and the human cDNA-expressed CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Supersomes). Activities of CYP enzymes were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), and testosterone 6ß-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of asenapine using HPLC. RESULTS: The obtained results showed that both in human liver microsomes and Supersomes asenapine potently and to a similar degree inhibited the activity of CYP1A2 via a mixed mechanism (Ki = 3.2 µM in liver microsomes and Supersomes) and CYP2D6 via a competitive mechanism (Ki = 1.75 and 1.89 µM in microsomes and Supersomes, respectively). Moreover, asenapine attenuated the CYP3A4 activity via a non-competitive mechanism (Ki = 31.3 and 27.3 µM in microsomes and Supersomes, respectively). In contrast, asenapine did not affect the activity of CYP2C9 or CYP2C19. CONCLUSION: The potent inhibition of CYP1A2 and CYP2D6 by asenapine, demonstrated in vitro, will most probably be observed also in vivo, since the calculated Ki values are close to the presumed concentration range for asenapine in the liver in vivo. Therefore, pharmacokinetic interactions involving asenapine and CYP2D6 or CYP1A2 substrates are likely to occur during their co-administration to patients.
Assuntos
Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Dibenzocicloeptenos , Interações Medicamentosas , Humanos , Microssomos HepáticosRESUMO
BACKGROUND: 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) demonstrates significant neuroprotective activity. It can interact with agonistic conformation of dopamine (DA) receptors. 1MeTIQ inhibits the formation of 3,4-dihydroxyphenylacetic acid as well as production of free radicals and shifts DA catabolism toward COMT-dependent O-methylation. 1MeTIQ inhibits both MAO-A and B enzymes activity and increases neurotransmitters levels in the brain. It shows significant antidepressant-like effect in forced swim test (FST) in rats. This compound might be effective for depression therapy in a clinical setting but its success is determined not only by good efficacy, but also by an acceptable its ADMET profile. The use of combination in silico prediction with in vivoand in vitro studies greatly simplifies the search for new, safer and effectively acting drugs. METHODS: The aim of this study was to investigate the degree of histopathological changes in different rats tissues after acute and chronic administration of 1MeTIQ. Additionally, prediction of its properties in terms of absorption, distribution, metabolism, elimination and toxicity in the human body was performed. RESULTS: The obtained data did not show extensive and significant toxic effects of tested substance in in vivo and in vitro studies in rats, and in silico ADMET prediction. CONCLUSIONS: These results can help to discover a new effective and safe antidepressant substance and have important significance in the treatment of depression in clinic. Additionally, the use in the treatment of depression substance with neuroprotective, antioxidant and antidepressant-like effects in the CNS and existing endogenously might be also beneficial in controlling the adverse CNS inflammatory processes accompanying depression.
Assuntos
Aminas/metabolismo , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/efeitos adversos , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Dopamina/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Natação/fisiologiaRESUMO
Consistent with their antagonistic actions at N-methyl-D-aspartate type glutamate receptors, dextromethorphan (DXM) and its metabolite, dextrorphan (DXT) decrease the intensity of opioid withdrawal syndrome. Since quinidine (QND) affects CYP2D6-mediated metabolism and P-glycoprotein governed transport, we sought to determine whether co-treatment with QND would affect brain levels of DXM and DXT as well as the effect of these compounds on opioid withdrawal syndrome in mice. We found that DXM dose dependently inhibited the intensity of opioid withdrawal syndrome and that there was a tendency for a further decrease when QND was co-administered with DXM. Administration of 30 mg/kg of DXM resulted in higher brain levels of DXM and DXT than administration of 10 mg/kg of DXM, but much lower DXT levels than that produced by 30 mg/kg of DXT. Co-treatment with QND resulted in higher brain levels of DXM (but not DXT) suggesting that QND produces an increase in the brain availability of DXM. In summary, brain levels of DXM were inversely correlated with the intensity of opioid withdrawal syndrome. QND induced increased brain levels of DXM tend to attenuate the intensity of opioid withdrawal syndrome. We suggest that it is DXM, rather than DXT, that is responsible for the attenuating effect on the intensity of opioid withdrawal syndrome, and that the beneficial action of QND on the effect of DXM should be more pronounced in humans.
Assuntos
Encéfalo/metabolismo , Dextrometorfano/farmacologia , Dextrometorfano/farmacocinética , Dextrorfano/farmacologia , Dextrorfano/farmacocinética , Dependência de Morfina/fisiopatologia , Morfina/toxicidade , Quinidina/farmacologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Masculino , Mastigação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Comportamento Estereotipado/efeitos dos fármacosRESUMO
The aim of the present study was to investigate the influence of antidepressants with different chemical structures and mechanisms of action affecting serotonergic and/or noradrenergic systems - tricyclic antidepressant drugs (TAD), selective serotonin reuptake inhibitors (SSRIs) and novel antidepressants (mirtazapine, nefazodone) - on the activity of rat CYP2B measured as the rate of 16beta-hydroxylation of testosterone. The reaction was studied in control liver microsomes in the presence of antidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10; desipramine, fluoxetine, sertraline 5; mirtazapine 3). The obtained K(i) values indicated that nefazodone and the SSRIs sertraline and fluoxetine were the most potent inhibitors of the studied reaction (K(i) = 10-20 microM). The inhibitory effects of TADs were modest (K(i) = 62-85 microM), while mirtazapine was a very weak inhibitor of CYP2B activity (K(i) = 286 microM). After a one-day exposure of rats to the investigated antidepressants, a significant increase in CYP2B activity was only observed after sertraline exposure (300% of the control). Chronic treatment with the antidepressants led to a significant enhancement of CYP2B activity after sertraline, fluoxetine and desipramine (580, 200 and 150% of the control, respectively) treatment, which positively correlated with the observed elevation in CYP2B protein levels. In summary, two different mechanisms of the antidepressant-CYP2B interaction are postulated: 1) a direct inhibition of CYP2B shown in vitro by nefazodone, SSRIs and TADs; 2) in vivo induction of CYP2B produced by prolonged administration of SSRIs and desipramine, which suggests their influence on enzyme regulation. The marked CYP2B-induction produced by SSRIs corresponds with their selective serotonin reuptake inhibition, while the effect of desipramine corresponds with its selective inhibition of noradrenaline reuptake.
Assuntos
Antidepressivos/farmacologia , Citocromo P-450 CYP2B1/metabolismo , Microssomos Hepáticos/enzimologia , Animais , Citocromo P-450 CYP2B1/antagonistas & inibidores , Indução Enzimática/efeitos dos fármacos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Our earlier study showed that damage to brain dopaminergic pathways causes decreases in CYP2B, CYP2C11 and CYP3A, as well as increases in CYP1A protein levels and activities in the liver. The aim of the present study was to investigate the influence of lesions of brain dopaminergic pathways on hormones and cytokines that are thought to mediate the effect of the dopaminergic system on liver CYP expression. At 48 h or 7 days after lesion of the tuberoinfundibular pathway, growth hormone level was significantly decreased, while the concentration of triiodothyronine was considerably increased. Fourteen days after lesion of the mesolimbic pathway, triiodothyronine level was significantly elevated, while corticosterone concentration was visibly reduced. The plasma levels of thyroxine, testosterone, interleukin-2, and interleukin-6 were not changed after lesion of the tuberoinfundibular or the mesolimbic pathways. The present study suggests that liver CYP is regulated by the dopaminergic tuberoinfundibular pathway via growth hormone and triiodothyronine, while the mesolimbic pathway influences this enzyme via corticosterone and triiodothyronine. Cytokines are not involved in the observed down-regulation of CYP isoforms after lesion of either dopaminergic pathway.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Dopamina/fisiologia , Isoenzimas/metabolismo , Fígado/enzimologia , Animais , Corticosterona/sangue , Citocinas/sangue , Hormônio do Crescimento/sangue , Masculino , Ratos , Ratos Wistar , Tri-Iodotironina/sangueRESUMO
Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.
Assuntos
Aminas/farmacologia , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Sulfonamidas/farmacologia , Aminas/síntese química , Aminas/química , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Cobaias , Células HEK293 , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Genes encoding different cytochrome P450 (CYP) isoforms are regulated by endogenous hormones (e.g. pituitary hormones, thyroid hormones, glucocorticoids) which are all under control of the central nervous system. The aim of the present study was to investigate the influence of lesions of brain dopaminergic pathways on the level and the activity of CYP isoforms (1A, 2A, 2B, 2C6, 2C11, 2D, 3A) in rat liver. At 48 h after lesion of the tuberoinfundibular pathway, only the activity and the protein level of CYP2B were significantly decreased. Seven days after lesion of the above-mentioned pathway, significant inhibition of CYP2B, CYP2C11 and CYP3A activities and a decrease in CYP protein levels were observed. At the same time, the activity and the protein level of CYP1A considerably increased. Fourteen days after damage of the mesolimbic pathway, the activity and the protein level of CYP3A were significantly reduced, while those of CYP1A were substantially elevated. In contrast, lesion of the nigrostriatal pathway did not affect any CYP isoforms studied. The obtained results provide the first direct evidence for the influence of brain dopaminergic system on the level and the activity of CYP in the liver, which is pathway- and isoform-dependent. Hence stimulation or inhibition of the brain dopaminergic system (e.g. by dopamine receptor-blocking neuroleptics) may cause changes in CYP activity of physiological, pharmacological and toxicological significance, since CYP isoforms that are regulated by the dopaminergic system catalyze the metabolism of endogenous substances (e.g. steroids), clinically important drugs (e.g. psychotropics, calcium channel antagonists, antibiotics) and toxins.
Assuntos
Encéfalo/fisiologia , Sistema Enzimático do Citocromo P-450/metabolismo , Dopamina/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Fígado/enzimologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Western Blotting , Química Encefálica/fisiologia , Sistema Enzimático do Citocromo P-450/genética , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Técnicas In Vitro , Isoenzimas/genética , Isoenzimas/metabolismo , Sistema Límbico/fisiologia , Masculino , Neostriado/fisiologia , Oxidopamina , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , SimpatolíticosRESUMO
Our previous studies showed that some of the tested antidepressants (tricyclics, SSRIs, mirtazapine, nefazodone) directly inhibited the metabolism of caffeine when added in vitro to liver microsomes. The aim of the present study was to investigate a possible indirect effect of prolonged in vivo administration of these antidepressants on the rate of caffeine oxidative metabolism: 1-N-, 3-N- and 7-N-demethylation and 8-hydroxylation in rat liver. The reactions were studied in liver microsomes of rats treated intraperitoneally (ip) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone at 10 mg/kg; desipramine, fluoxetine, sertraline at 5 mg/kg; mirtazapine at 3 mg/kg), in the absence of the antidepressants in vitro. One-day treatment with imipramine and amitriptyline decreased, while fluoxetine accelerated the metabolism of caffeine. Nefazodone stimulated 1-N-demethylation only. Fluoxetine given chronically increased exclusively 7-N-demethylation, while imipramine showed only such tendency. Sertraline and mirtazapine enhanced the rates of all caffeine oxidation pathways. We conclude that the tested antidepressant drugs may affect the metabolism of caffeine not only in a direct way (binding to the enzyme), but also indirectly via inducing CYP1A2 (sertraline and mirtazapine) and CYP2C isoforms (fluoxetine, sertraline, mirtazapine) after prolonged administration. In addition, the presented data provide further experimental evidence for the importance of the subfamily CYP2C for the 7-N-demethylation of caffeine in the rat.
Assuntos
Antidepressivos/farmacologia , Cafeína/metabolismo , Animais , Antidepressivos/administração & dosagem , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacologia , Cafeína/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Esquema de Medicação , Hidroxilação , Técnicas In Vitro , Injeções Intraperitoneais , Masculino , Metilação , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2B measured as a rate of 16 beta-hydroxylation of testosterone. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine and perazine, 10 each; chlorpromazine 3; haloperidol 0.3; risperidone 0.1; sertindole 0.05), in the absence of the neuroleptics in vitro. ome of the neuroleptics added in vitro to control liver microsomes decreased the activity of CYP2B. The obtained Ki values indicated that thioridazine was the most potent inhibitor of the studied reaction (Ki = 26 microM). The inhibitory effects of chlorpromazine, perazine and sertindole were moderate (Ki = 45-75 microM), while promazine, haloperidol, levomepromazine, and risperidone were rather weak inhibitors of CYP2B activity (Ki = 125-225 microM, respectively). After a one-day (i.e. 24 h) exposure of rats to the investigated neuroleptics, the decreased CYP2B activity was observed after haloperidol, risperidone and sertindole. All the investigated neuroleptics did not produce any significant effect on CYP2B activity when administered in vivo for two weeks. Considering relatively high pharmacological/therapeutic doses and liver concentrations of phenothiazines, it seems that the direct inhibitory effect of those neuroleptics with Ki values below 100 microM found in vitro (thioridazine, chlorpromazine, perazine), as well as indirect effects produced by one-day treatment with haloperidol, risperidone or sertindole may be of some physiological, pharmacological or toxicological importance in vivo.
Assuntos
Antipsicóticos/farmacologia , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2B1/metabolismo , Fígado/efeitos dos fármacos , Esteroide Hidroxilases/metabolismo , Animais , Técnicas In Vitro , Isoenzimas/metabolismo , Fígado/enzimologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Ratos , Ratos Wistar , Testosterona/metabolismoRESUMO
The paper describes the effect of amantadine addition to imipramine therapy in patients suffering from treatment-resistant unipolar depression who fulfilled DSM IV criteria for major (unipolar) depression. Fifty patients were enrolled in the study on the basis of their histories of illness and therapy. After a 2-week drug-free period, 25 subjects belonging to the first group were treated only with imipramine twice daily (100 mg/day) for 12 weeks, and 25 subjects belonging to the second group were treated with imipramine twice daily (100 mg/day) for 6 weeks and then amantadine was introduced (150 mg/day, twice daily) and administered jointly with imipramine for the successive 6 weeks. Hamilton Depression Rating Scale (HDRS) was used to assess the efficacy of antidepressant therapy. Imipramine did not change the HDRS score after 3, 6 or 12 weeks of treatment when compared with the washout (before treatment). The addition of amantadine to the classic antidepressant reduced HDRS scores after 6-week joint treatment. Moreover, the obtained pharmacokinetic data indicated that amantadine did not significantly influence the plasma concentration of imipramine and its metabolite desipramine in patients treated jointly with imipramine and amantadine, which suggests lack of a pharmacokinetic interaction. The obtained results indicate that joint therapy with an antidepressant and amantadine may be effective in treatment-resistant unipolar depression.
Assuntos
Amantadina/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Dopaminérgicos/uso terapêutico , Imipramina/uso terapêutico , Adulto , Amantadina/administração & dosagem , Amantadina/sangue , Antidepressivos/administração & dosagem , Antidepressivos/sangue , Cromatografia Líquida de Alta Pressão , Dopaminérgicos/administração & dosagem , Dopaminérgicos/sangue , Resistência a Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Imipramina/administração & dosagem , Imipramina/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
In the present study, we sought to determine whether chronic treatment with perazine alters lipopolysaccharide (LPS)-induced interleukin-1 beta (IL-1 beta) levels in the following rat brain regions: the hypothalamus, frontal cortex, striatum and hippocampus. Male Wistar rats were administered perazine dimaleate (15 or 30 mg/kg/day) in drinking water for 21 days. On day 22, LPS was injected i.p. (125 microg/kg) 2 h before decapitation. Concentrations of perazine and its metabolites in plasma and brain was assessed by HPLC. The levels of IL-1 beta were determined using ELISA. Treatment with perazine (30 mg/kg/day) reduced LPS-stimulated IL-1 beta levels in the hypothalamus, and a tendency to its decrease in the striatum and frontal cortex was observed. This in vivo study suggests for the first time that long-term oral administration of perazine modulates reactivity of cells producing IL-1 beta.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Interleucina-1beta/análise , Lipopolissacarídeos/farmacologia , Perazina/farmacologia , Animais , Encéfalo/imunologia , Relação Dose-Resposta a Droga , Interleucina-1beta/biossíntese , Masculino , Ratos , Ratos WistarRESUMO
Our recent work showed that the brain serotonergic system negatively regulated liver cytochrome P450. The aim of our present research was to study the effect of damage to the serotonergic innervation of the paraventricular (PVN) or arcuate nuclei (ARC) of the hypothalamus on the neuroendocrine regulation of cytochrome P450 (CYP). Male rats received bilateral injections of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the PVN or ARC. One week after the injection brain neurotransmitters, serum hormones (growth hormone, testosterone, corticosterone, thyroid hormones), pituitary somatostatin and liver cytochrome P450 expression and activity were measured. Lesion of the serotonergic innervation of the PVN decreased serotonin level in the hypothalamic area containing the PVN, causing an increase in growth hormone and testosterone concentrations in the blood and, subsequently, an increase in the expression (mRNA and protein level) and activity of isoform CYP2C11 in the liver. In contrast, damage to the serotonergic innervation of the ARC, which caused a decrease in serotonin level in the hypothalamic area containing the ARC, reduced the concentration of growth hormone and the expression and activity of CYP2C11. In conclusion, the obtained results show a reverse effect of the serotonergic innervation of the hypothalamic paraventricular (a negative effect) and arcuate nuclei (a positive effect) on growth hormone secretion and growth hormone-dependent CYP2C11 expression. They also suggest that CYP2C11 expression may be changed by drugs acting via the serotonergic system, their effect depending on their mechanism of action, route of administration (intracerebral, peripheral) and distribution pattern within the hypothalamus.