RESUMO
Cytochrome P450 (CYP) enzymes are involved in the metabolism of approximately 75% of marketed drugs. Inhibition of the major drug-metabolizing P450s could alter drug metabolism and lead to undesirable drug-drug interactions. Therefore, it is of great significance to explore the inhibition of P450s in drug discovery. Currently, machine learning including deep learning algorithms has been widely used for constructing in silico models for the prediction of P450 inhibition. These models exhibited varying predictive performance depending on the use of machine learning algorithms and molecular representations. This leads to the difficulty in the selection of appropriate models for practical use. In this study, we systematically evaluated the conventional machine learning and deep learning models for three major P450 enzymes, CYP3A4, CYP2D6, and CYP2C9 from several perspectives, such as algorithms, molecular representation, and data partitioning strategies. Our results showed that the XGBoost and CatBoost algorithms coupled with the combined fingerprint/physicochemical descriptor features exhibited the best performance with Area Under Curve (AUC) of 0.92, while the deep learning models were generally inferior to the conventional machine learning models (average AUC reached 0.89) on the same test sets. We also found that data volume and sampling strategy had a minor effect on model performance. We anticipate that these results are helpful for the selection of molecular representations and machine learning/deep learning algorithms in the P450 model construction and the future model development of P450 inhibition.
Assuntos
Aprendizado de Máquina , Humanos , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Algoritmos , Aprendizado Profundo , Simulação por Computador , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologiaRESUMO
This study aimed to explore the cytochrome P450 (CYP) metabolic and inhibitory profile of hydroxychloroquine (HCQ). Hydroxychloroquine metabolism was studied using human liver microsomes (HLMs) and recombinant CYP enzymes. The inhibitory effects of HCQ and its metabolites on nine CYPs were also determined in HLMs, using an automated substrate cocktail method. Our metabolism data indicated that CYP3A4, CYP2D6, and CYP2C8 are the key enzymes involved in HCQ metabolism. All three CYPs formed the primary metabolites desethylchloroquine (DCQ) and desethylhydroxychloroquine (DHCQ) to various degrees. Although the intrinsic clearance (CLint) value of HCQ depletion by recombinant CYP2D6 was > 10-fold higher than that by CYP3A4 (0.87 versus 0.075 µl/min/pmol), scaling of recombinant CYP CLint to HLM level resulted in almost equal HLM CLint values for CYP2D6 and CYP3A4 (11 and 14 µl/min/mg, respectively). The scaled HLM CLint of CYP2C8 was 5.7 µl/min/mg. Data from HLM experiments with CYP-selective inhibitors also suggested relatively equal roles for CYP2D6 and CYP3A4 in HCQ metabolism, with a smaller contribution by CYP2C8. In CYP inhibition experiments, HCQ, DCQ, DHCQ, and the secondary metabolite didesethylchloroquine were direct CYP2D6 inhibitors, with 50% inhibitory concentration (IC50) values between 18 and 135 µM. HCQ did not inhibit other CYPs. Furthermore, all metabolites were time-dependent CYP3A inhibitors (IC50 shift 2.2-3.4). To conclude, HCQ is metabolized by CYP3A4, CYP2D6, and CYP2C8 in vitro. HCQ and its metabolites are reversible CYP2D6 inhibitors, and HCQ metabolites are time-dependent CYP3A inhibitors. These data can be used to improve physiologically-based pharmacokinetic models and update drug-drug interaction risk estimations for HCQ. SIGNIFICANCE STATEMENT: While CYP2D6, CYP3A4, and CYP2C8 have been shown to mediate chloroquine biotransformation, it appears that the role of CYP enzymes in hydroxychloroquine (HCQ) metabolism has not been studied. In addition, little is known about the CYP inhibitory effects of HCQ. Here, we demonstrate that CYP2D6, CYP3A4, and CYP2C8 are the key enzymes involved in HCQ metabolism. Furthermore, our findings show that HCQ and its metabolites are inhibitors of CYP2D6, which likely explains the previously observed interaction between HCQ and metoprolol.
Assuntos
Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Hidroxicloroquina/metabolismo , Hidroxicloroquina/farmacologia , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Microssomos Hepáticos/metabolismoRESUMO
Recently, it has been reported that tipepidine has various central pharmacological effects and can be expected to be safely repositioned as a treatment for psychiatric disorders. Since tipepidine has a very short half-life and requires three doses per day, the development of a once-daily medication would be highly beneficial to improve adherence and quality of life in patients with chronic psychiatric disorders. The aim of this study was to identify the enzymes involved in tipepidine metabolism and to verify that combination use with an enzyme inhibitor prolongs the half-life of tipepidine.Metabolism studies using recombinant human cytochrome P450 (P450, CYP) isoforms and inhibition studies using various selective P450 inhibitors and human liver microsomes revealed that CYP2D6 is the main enzyme catalysing tipepidine metabolism, with a metabolic contribution ratio of 85.4%.Furthermore, a pharmacokinetic study using chimeric mice with humanised liver showed that oral coadministration of a CYP2D6 inhibitor, quinidine, increased the Cmax, AUC0-t, and t1/2 of tipepidine by 1.5-, 3.2-, and 3.0-fold, respectively.These results indicated that coadministration of a CYP2D6 inhibitor is effective in increasing plasma exposure and prolonging the half-life of tipepidine and is useful for repositioning tipepidine as a treatment for psychiatric disorders.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2D6 , Humanos , Camundongos , Animais , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Meia-Vida , Qualidade de Vida , Inibidores Enzimáticos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/metabolismo , Microssomos Hepáticos/metabolismoRESUMO
INTRODUCTION: In recent years, oral antineoplastic agents are commonly used in antitumor therapy. The interaction between drugs may affect the efficacy of drugs or lead to adverse reactions. We describe the case of a patient who presented acute liver injury, possibly induced by the concomitant use of metoprolol and dacomitinib. CASE REPORT: A 62-year-old male patient with non-small cell lung cancer was admitted for anti-cancer treatment. He regularly took metoprolol tartrate 12.5â mg, 2/day for hypertension. He was treated with dacomitinib according to EGFR Exon21 L858R positive. After 3 days of dacomitinib, the patient's alanine aminotransferase (ALT) and glutathione aminotransferase (AST) increased, and the heart rate and systolic blood pressure of the patient decreased significantly. The patient was diagnosed with acute liver injury. MANAGEMENT AND OUTCOMES: Dacomitinib was discontinued and glutathione, magnesium isoglycyrrhizinate were given to treat acute liver injury. Two days after discontinued dacomitinib, the patient's heart rate increased, but the ALT and AST of the patient elevated again. Metoprolol tartrate was subsequently discontinued and the ALT and AST gradually decreased and the patient discharged from the hospital eight days later with his liver function improved. DISCUSSION: To our knowledge, this is the first case in the literature of acute liver injury possibly induced by the interaction between metoprolol and dacomitinib. The interaction most likely arose because dacomitinib is a CYP2D6 strong inhibitor and could therefore impair the metabolism of metoprolol (a CYP2D6 substrate) and increase its serum concentration. Therefore, hepatic function should be carefully monitored in patients treated with dacomitinib and metoprolol and other inhibitors or inducers of CYP2D6.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Pessoa de Meia-Idade , Metoprolol/efeitos adversos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Interações Medicamentosas , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , FígadoRESUMO
We aim to study the effects of CYP2D6 variants and drug-drug interaction on the metabolism of dacomitinib. CYP2D6 variants were incubated with 25-1000 µM dacomitinib for 40 min at 37 °C, and the reaction was terminated by cooling to -80 °C immediately. For an in vivo experiment, 18 male Sprague-Dawley rats were randomly divided into three groups (n = 6): a single dose of 5 mg/kg dacomitinib (group A), a single dose of 6 mg/kg trazodone (group B), and a combined group (group C). Processed samples were analyzed by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS.) The relative clearance of dacomitinib was reduced for most of the variants. Moreover, the inhibitory potency of classic CYP inhibitors on dacomitinib metabolism was significantly different among the main subtypes of CYP2D6. Interestingly, compared with gefitinib, even the same CYP2D6 variants showed significant differences in metabolic activity, suggesting that the activity of CYP2D6 has strong variability. In addition, the interaction between trazodone and dacomitinib was determined both in vitro and in vivo. When dacomitinib was given in combination with trazodone, the blood exposure to these two drugs increased remarkably. The mechanistic study revealed that the interaction followed the noncompetitive inhibition. We demonstrated that the activity of CYP2D6 variants to metabolize dacomitinib was significantly reduced. In combination with the CYP2D6 inhibitor, the degree of activity inhibition of different variants obviously differed. When trazodone and dacomitinib were used in combination, the body exposure to the two drugs increased significantly. This study provides data for the precise use of dacomitinib in clinical settings.
Assuntos
Inibidores do Citocromo P-450 CYP2D6/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Polimorfismo Genético/efeitos dos fármacos , Quinazolinonas/farmacologia , Animais , Citocromo P-450 CYP2D6/genética , Inibidores do Citocromo P-450 CYP2D6/química , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Polimorfismo Genético/genética , Quinazolinonas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
PURPOSE: Deutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and ß-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites. METHODS: In this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.5-mg oral dose on days 1 and 11 and a single paroxetine 20-mg oral daily dose on days 4-12. Pharmacokinetics of deutetrabenazine and its metabolites were assessed on days 1-4 and 11-14. Paroxetine trough concentrations were obtained pre-dose on days 9-13. Safety examinations occurred throughout the study. RESULTS: Paroxetine administered under steady-state conditions, increased exposure of the deuterated active metabolites, α-HTBZ (1.2-fold Cmax and 1.8-fold AUC0-∞) and ß-HTBZ (2.1-fold Cmax and 5.6-fold AUC0-∞), and correspondingly, 1.6-fold Cmax and threefold AUC0-∞ for total (α + ß)-HTBZ. Sixteen subjects reported 45 adverse events and most were mild. Headache was the most common AE reported 8 times by 7 subjects (5 following paroxetine alone; 2 following deutetrabenazine + paroxetine). CONCLUSIONS: Paroxetine-induced increases in exposure to the active deutetrabenazine metabolites were less than those previously reported for tetrabenazine, a finding expected to reduce the burden of drug interaction. In addition, single doses of 22.5 mg deutetrabenazine, when given alone or in the presence of steady-state paroxetine (20 mg daily), were safe.
Assuntos
Inibidores do Citocromo P-450 CYP2D6/farmacologia , Paroxetina/farmacologia , Tetrabenazina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/farmacocinética , Adulto , Área Sob a Curva , Citocromo P-450 CYP2D6/metabolismo , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Tetrabenazina/farmacocinéticaRESUMO
PURPOSE: To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. METHODS: The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. RESULTS: The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% (P < 0.001) after 5 years and by 40% (P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54-0.69) and OR 0.45 (95% CI 0.40-0.51), respectively, versus OR 0.84 (95% CI 0.74-0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. CONCLUSION: The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2D6 , Interações Medicamentosas , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Atenolol , Bisoprolol , Bupropiona/uso terapêutico , Citocromo P-450 CYP2D6/genética , Inibidores do Citocromo P-450 CYP2D6/efeitos adversos , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , Prescrições de Medicamentos , Fluoxetina/uso terapêutico , Humanos , Metoprolol/efeitos adversos , Paroxetina/uso terapêutico , Estudos RetrospectivosRESUMO
PURPOSE: The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. METHODS: Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included. FINDINGS: A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater. CONCLUSIONS: Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.
Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Bupropiona/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Depressão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos de Segunda Geração/farmacologia , Bupropiona/farmacologia , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Succinato de Desvenlafaxina/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Cloridrato de Venlafaxina/administração & dosagem , Adulto JovemRESUMO
Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed, synthesized and biologically evaluated for their potential anticancer activity. All target compounds were evaluated in vitro for VEGFR-2 tyrosine kinase inhibition. Then, nine compounds of best results were further investigated by in vitro assay against three human cancer cell lines, namely HepG2, PC3 and MCF. N'-{2-](3-Ethyl-6-nitro-4-oxo-3,4-dihydroquinazoline-2-yl)thio[acetyl}benzohydrazide (36) was found to be the most potent candidate as it showed IC50 = 4.6 ± 0.06 µM against VEGFR-2 kinase. It also exhibited IC50 = 17.23 ± 1.5, 26.10 ± 2.2 and 30.85 ± 2.3 µg/mL against HepG2, PC3 and MCF, respectively. At the same time it showed IC50 = 145.93 ± 1.1 µg/mL against the normal human lung fibroblasts cell line (WI-38), indicating good selectivity index. Further investigation into HepG2 cell cycle showed the ability of compound 36 to induce apoptosis and arrest cell growth at G2/M phase. Moreover, docking studies demonstrated the ability of compound 36 to bind VEGFR-2 in a correct manner making three essential hydrogen bonds with the key residues Glu885, Asp1046 and Cys919. In sum, this work suggests that compound 36 can serve as a lead for development of effective anticancer agents targeting VEGFR-2.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/química , Linhagem Celular Tumoral , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/química , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação ProteicaRESUMO
This study used human liver microsomes to assess pterostilbene's effect on the metabolic activity of cytochrome P450 (CYP) 1A2, CYP2C9, and CYP2D6. The metabolism of their substrates (phenacetin, tolbutamide, and dextromethorphan) was assayed by quantifying their relevant metabolites by HPLC. The IC50 value was used to express the strength of inhibition, and the value of a volume per dose index (VDI) was used to indicate the metabolic ability of the enzyme. In this study, pterostilbene inhibited CYP1A2, CYP2C9, and CYP2D6's metabolic activities in vitro. CYP2C9's activity was most significantly inhibited by pterostilbene; its IC50 value was 0.12±0.04 µM. The IC50 value of CYP1A2 and CYP2D6 was 56.3±10.4 µM and 62.33±11.4 µM, respectively. The finding that suggests that pterostilbene has the potential to interact with CYP2C9 substrates in vivo. These results warrant clinical studies to assess the in vivo significance of these interactions.
Assuntos
Inibidores do Citocromo P-450 CYP1A2/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Estilbenos/farmacologia , Citocromo P-450 CYP1A2/efeitos dos fármacos , Citocromo P-450 CYP1A2/metabolismo , Inibidores do Citocromo P-450 CYP1A2/administração & dosagem , Citocromo P-450 CYP2C9/efeitos dos fármacos , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estilbenos/administração & dosagemRESUMO
The efficacy of aripiprazole therapy and the risk of adverse reactions are influenced by substantial inter-individual variability in aripiprazole metabolizing capacity. In vitro studies assigned the potential role in aripiprazole metabolism to CYP2D6 and CYP3A enzymes; therefore, the association between the steady-state aripiprazole plasma concentrations and patients' CYP2D6 and CYP3A statuses (CYP2D6, CYP3A4, and CYP3A5 genotypes, and CYP3A4 expression) and/or co-medication with CYP function modifying medications has been investigated in 93 psychiatric patients on stable aripiprazole therapy. The patients' CYP2D6 genotype had a major effect on aripiprazole plasma concentrations, whereas contribution of CYP3A genotypes and CYP3A4 expression to aripiprazole clearance were considered to be minor or negligible. The role of CYP3A4 expression in aripiprazole metabolism did not predominate even in the patients with nonfunctional CYP2D6 alleles. Furthermore, dehydroaripiprazole exposure was also CYP2D6 genotype-dependent. Dehydroaripiprazole concentrations were comparable with aripiprazole levels in patients with functional CYP2D6 alleles, and 35% or 22% of aripiprazole concentrations in patients with one or two non-functional CYP2D6 alleles, respectively. The concomitant intake of CYP2D6 inhibitors, risperidone, metoprolol, or propranolol was found to increase aripiprazole concentrations in patients with at least one wild-type CYP2D6*1 allele. Risperidone and 9-hydroxy-risperidone inhibited both dehydrogenation and hydroxylation of aripiprazole, whereas metoprolol and propranolol blocked merely the formation of the active dehydroaripiprazole metabolite, switching towards the inactivation pathways. Patients' CYP2D6 genotype and co-medication with CYP2D6 inhibitors can be considered to be the major determinants of aripiprazole pharmacokinetics. Taking into account CYP2D6 genotype and co-medication with CYP2D6 inhibitors may improve the outcomes of aripiprazole therapy.
Assuntos
Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Transtorno Bipolar/tratamento farmacológico , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Citocromo P-450 CYP2D6 , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
CONTEXT: Succinic acid, extracted from amber, is widely used in cardiovascular therapy. OBJECTIVE: The effect of succinic acid on the activity of cytochrome P450 (CYP450) enzymes was investigated in this study. MATERIALS AND METHODS: The effect of succinic acid (100 µM) on the activity of eight isoforms of CYP450 (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) was investigated compared to the specific inhibitor and blank controls in pooled human liver microsomes in vitro. The inhibition of CYPs was fitted with competitive or non-competitive inhibition models and corresponding parameters were also obtained. RESULTS: Succinic acid exerted inhibitory effect on the activity of CYP3A4, 2D6, and 2C9 with the IC50 values of 12.82, 14.53, and 19.60 µM, respectively. Succinic acid inhibited the activity of CYP3A4 in a non-competitive manner with the Ki value of 6.18 µM, and inhibited CYP2D6 and 2C9 competitively with Ki values of 7.40 and 9.48 µM, respectively. Furthermore, the inhibition of CYP3A4 was found to be time-dependent with the KI/Kinact value of 6.52/0.051 min-1·µM-1. DISCUSSION AND CONCLUSIONS: Succinic acid showed in vitro inhibitory effects on the activity of CYP3A4, 2D6, and 2C9, which indicated the potential drug-drug interactions. Succinic acid should be carefully co-administrated with the drugs metabolized by CYP3A4, 2D6, and 2C9.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Ácido Succínico/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Humanos , CinéticaRESUMO
PURPOSE: Tamoxifen is one of the principal treatments for estrogen receptor (ER)-positive breast cancer. Unfortunately, between 30 and 50% of patients receiving this hormonal therapy relapse. Since CYP2D6 genetic variants have been reported to play an important role in survival outcomes after treatment with tamoxifen, this study sought to summarize and critically appraise the available scientific evidence on this topic. METHODS: A systematic literature review was conducted to identify studies investigating associations between CYP2D6 genetic variation and survival outcomes after tamoxifen treatment. Critical appraisal of the retrieved scientific evidence was performed, and recommendations were developed for CYP2D6 genetic testing in the context of tamoxifen therapy. RESULTS: Although conflicting literature exists, the majority of the current evidence points toward CYP2D6 genetic variation affecting survival outcomes after tamoxifen treatment. Of note, review of the CYP2D6 genotyping assays used in each of the studies revealed the importance of comprehensive genotyping strategies to accurately predict CYP2D6 metabolizer phenotypes. CONCLUSIONS AND RECOMMENDATIONS: Critical appraisal of the literature provided evidence for the value of comprehensive CYP2D6 genotyping panels in guiding treatment decisions for non-metastatic ER-positive breast cancer patients. Based on this information, it is recommended that alternatives to standard tamoxifen treatments may be considered in CYP2D6 poor or intermediate metabolizers.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Citocromo P-450 CYP2D6/genética , Variação Genética , Receptores de Estrogênio/genética , Alelos , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Tomada de Decisão Clínica , Fatores de Confusão Epidemiológicos , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , Gerenciamento Clínico , Feminino , Genótipo , Humanos , Farmacogenética , Guias de Prática Clínica como Assunto , Prognóstico , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêuticoRESUMO
PURPOSE: Tamoxifen is widely used to reduce the risk of breast cancer (BC) recurrence and extend disease-free survival among women with estrogen-sensitive breast cancers. Tamoxifen efficacy is thought to be attributable to its active metabolite, which is formed through a reaction catalyzed by the P450 enzyme, CYP2D6. Inhibition of tamoxifen metabolism as a result of germline genetic variation and/or use of CYP2D6-inhibiting medications ("inhibitors") is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen. METHODS: The present cohort study of 960 women diagnosed with early-stage BC between 1993 and 1999 examined the association between concomitant use of CYP2D6 inhibitors and adjuvant tamoxifen and the risk of adverse BC outcomes (recurrence, second primary BC, BC mortality), both overall and according to CYP2D6 metabolic phenotype. RESULTS: Six or more months of CYP2D6 inhibitor use concomitant with tamoxifen was not associated with any appreciable increase in risk of recurrence or second primary BC or BC mortality, and there was no clear evidence of variation by CYP2D6 metabolic phenotype. CONCLUSIONS: These results are consistent with the relatively few other large, population-based studies conducted to date that have not observed an increased risk of adverse BC outcomes associated with CYP2D6 inhibition.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Tamoxifeno/uso terapêutico , Idoso , Neoplasias da Mama/genética , Estudos de Coortes , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , FenótipoRESUMO
Benzalkonium chlorides (BACs) are widely used as disinfectants in cleaning products, medical products, and the food processing industry. Despite a wide range of reported toxicities, limited studies have been conducted on the metabolism of these compounds in animal models and none in human-derived cells or tissues. In this work, we report on the metabolism of BACs in human liver microsomes (HLM) and by recombinant human hepatic cytochrome P450 (CYP) enzymes. BAC metabolism in HLM was NADPH-dependent and displayed apparent half-lives that increased with BAC alkyl chain length (C10 < C12 < C14 < C16), suggesting enhanced metabolic stability of the more lipophilic, longer chain BACs. Metabolites of d7-benzyl labeled BAC substrates retained all deuteriums and there was no evidence of N-dealkylation. Tandem mass spectrometry fragmentation of BAC metabolites confirmed that oxidation occurs on the alkyl chain region. Major metabolites of C10-BAC were identified as ω-hydroxy-, (ω-1)-hydroxy-, (ω, ω-1)-diol-, (ω-1)-ketone-, and ω-carboxylic acid-C10-BAC by liquid chromatography-mass spectrometry comparison with synthetic standards. In a screen of hepatic CYP isoforms, recombinant CYP2D6, CYP4F2, and CYP4F12 consumed substantial quantities of BAC substrates and produced the major microsomal metabolites. The use of potent pan-CYP4 inhibitor HET0016, the specific CYP2D6 inhibitor quinidine, or both confirmed major contributions of CYP4- and CYP2D6-mediated metabolism in the microsomal disappearance of BACs. Kinetic characterization of C10-BAC metabolite formation in HLM demonstrated robust Michaelis-Menten kinetic parameters for ω-hydroxylation (Vmax = 380 pmol/min/mg, Km = 0.69 µM) and (ω-1)-hydroxylation (Vmax = 126 pmol/min/mg, Km = 0.13 µM) reactions. This work illustrates important roles for CYP4-mediated ω-hydroxylation and CYP2D6/CYP4-mediated (ω-1)-hydroxylation during the hepatic elimination of BACs, an environmental contaminant of emerging concern. Furthermore, we demonstrate that CYP-mediated oxidation of C10-BAC mitigates the potent inhibition of cholesterol biosynthesis exhibited by this short-chain BAC.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Compostos de Benzalcônio/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Desinfetantes/metabolismo , Amidinas/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/química , Compostos de Benzalcônio/química , Isótopos de Carbono/química , Citocromo P-450 CYP2D6/química , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Feminino , Humanos , Hidroxilação/efeitos dos fármacos , Cinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Oxirredução , Quinidina/farmacologiaRESUMO
Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (Roxb.) DC, a widely used traditional herbal medicine. Several reports have revealed NC's multiple pharmacologic properties. The inhibitory effects of NC on human cytochrome P450 enzymes were investigated in the present study. We found that NC caused time- and concentration-dependent inhibition of CYP2D6, and more than 50% of CYP2D6 activity was suppressed after a 15-minute incubation with NC at 100 µM in the primary incubation mixtures, with KI of 4.36 µM, kinact of 0.052 minute-1, and a partition ratio of approximately 290. Moreover, the loss of CYP2D6 activity required the presence of NADPH. Superoxide dismutase/catalase and glutathione showed minor protection against the NC-induced enzyme inhibition. Quinidine as a competitive inhibitor of CYP2D6 slowed down the inactivation by NC. Trapping experiments using N-acetylcysteine demonstrated that quinone and/or carbene intermediate(s) were/was generated in human liver microsomal incubations with NC. In addition, potassium ferricyanide prevented the enzyme from the inactivation mediated by NC, which provided evidence that inhibition of CYP2D6 resulted from heme destruction by the formation of a carbene-iron complex. CYP1A2 was found to be the major enzyme involved in the generation of NC quinone metabolites. In conclusion, NC is a mechanism-based inactivator of CYP2D6. The generation of a carbene intermediate might be mainly responsible for the enzyme inactivation.
Assuntos
Benzofenantridinas/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Catalase/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Glutationa/metabolismo , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , NADP/metabolismo , Quinidina/farmacologia , Superóxido Dismutase/metabolismoRESUMO
AIMS: Pridopidine is an oral drug in clinical development for treatment of patients with Huntington's disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed. METHODS: The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolizing enzymes was examined in human liver microsomes and fresh hepatocytes. CYP2D6 inhibition potency and reversibility was assessed using dextromethorphan. For the clinical assessment, 22 healthy subjects were given metoprolol 100 mg alone and concomitantly with steady-state pridopidine 45 mg twice daily. Food effect on a single 90 mg dose of pridopidine was evaluated in a crossover manner. Safety assessments and pharmacokinetic sampling occurred throughout the study. RESULTS: Pridopidine was found to be a metabolism dependent inhibitor of CYP2D6, the main enzyme catalysing its own metabolism. Flavin-containing monooxygenase heat inactivation of liver microsomes did not affect pridopidine metabolism-dependent inhibition of CYP2D6 and its inhibition of CYP2D6 was not reversible with addition of FeCN3 . Exposure to metoprolol was markedly increased when coadministered with pridopidine; the ratio of the geometric means (90% confidence interval) for maximum observed plasma concentration, and area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration and extrapolated to infinity were 3.5 (2.9, 4.22), 6.64 (5.27, 8.38) and 6.55 (5.18, 8.28), respectively. Systemic exposure to pridopidine was unaffected by food conditions. CONCLUSIONS: As pridopidine is a metabolism-dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic coadministration of pridopidine. Pridopidine can be administered without regard to food.
Assuntos
Inibidores do Citocromo P-450 CYP2D6/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Interações Alimento-Droga , Doença de Huntington/tratamento farmacológico , Metoprolol/farmacologia , Piperidinas/farmacologia , Área Sob a Curva , Células Cultivadas , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , Dextrometorfano/farmacologia , Interações Medicamentosas , Feminino , Ferricianetos/farmacologia , Voluntários Saudáveis , Hepatócitos , Humanos , Masculino , Microssomos Hepáticos , Pessoa de Meia-Idade , Piperidinas/uso terapêuticoRESUMO
BACKGROUND: Although clinically widespread, scientific evidence for antipsychotic polypharmacy is still limited. Combining different drugs increases the potential for drug-drug interactions, enhancing the risk of adverse drug reactions. We aimed to unravel the potential pharmacokinetic interactions between risperidone (RIS) and perazine. METHODS: Using a therapeutic drug monitoring database containing plasma concentrations of RIS and its active metabolite [9-hydroxyrisperidone (9-OH-RIS)], we considered two groups: a group of patients under antipsychotic monotherapy with RIS (n = 40) and a group of patients that was comedicated with perazine (n = 16). Groups were matched for demographic characteristics and daily dosage of RIS. Plasma concentrations, concentrations corrected for the dose (C/D) of RIS, 9-OH-RIS and the active moiety (RIS + 9-OH-RIS), as well as the metabolic ratios of concentrations of 9-OH-RIS/RIS, were compared using nonparametric tests. RESULTS: All parameters other than plasma concentrations and the C/D ratio of 9-OH-RIS differed between groups. Median values for plasma concentrations of the active moiety and C/D of the active moiety were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Differences were driven by variations in the plasma concentrations and C/D of RIS, which were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Metabolic ratios were lower in the perazine group (P = 0.003). DISCUSSION: The coadministration of perazine in RIS-medicated patients leads to significantly higher plasma concentrations and C/D values of RIS and its active moiety, and a lower metabolic ratio, reflecting the cytochrome P450 (CYP) 2D6 phenotype. We suggest that the mechanism underlying the effect of perazine on RIS metabolism is based on an inhibition of CYP2D6 and CYP3A4 activity.
Assuntos
Antipsicóticos/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Transtornos Mentais/tratamento farmacológico , Polimedicação , Adulto , Antipsicóticos/sangue , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/sangue , Palmitato de Paliperidona/farmacologia , Perazina/farmacologia , Estudos Retrospectivos , Risperidona/sangue , Risperidona/farmacologiaRESUMO
Fluoxetine, a selective serotonin reuptake inhibitor antidepressant, modulates the mitogen-induced proliferation of lymphocytes. Lymphocytes contain taurine and express taurine transporter (TauT). Among the effects of taurine on lymphocytes are protection against oxidants and regulation of the inflammatory aspects of the immune response. Our aim was to determine the influence of fluoxetine treatment on taurine transport, and to determine the presence of TauT in the mononuclear cells of rats. METHODS: Male adult Sprague-Dawley rats were treated with fluoxetine 10 mg/kg i.p. for 1, 2, and 3 weeks. The cells were obtained by density gradients. [3H]Taurine was used for transport assays. Amino acid levels were determined by high-performance liquid chromatography. Immunolabeling of CD4+, CD8+, and TauT was performed. The mRNA of TauT was evaluated by RT-PCR. Controls were included for each protocol. RESULTS: The transport of taurine, after 1 week of treatment, was significantly augmented compared to controls. The affinity significantly increased at 1 and 2 weeks. While the percentage of CD4+ cells decreased and that of CD8+ cells increased, the percentage of TauT in CD4+ and CD8+ cells was not affected. Reduction of levels of aspartic acid, glutamic acid, threonine, alanine, glycine, and arginine occurred at 1 and 2 weeks. The taurine concentration significantly decreased after 2 and 3 weeks of treatment. The estimation of mRNA of TauT was not different. CONCLUSION: Taurine transport increases with fluoxetine treatment, and so this could be related to an immunomodulatory role of fluoxetine through TauT. Inhibition of serotonin reuptake might be involved in the regulation of taurine transport in mononuclear cells.
Assuntos
Inibidores do Citocromo P-450 CYP2D6/farmacologia , Fluoxetina/farmacologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Aminoácidos/metabolismo , Análise de Variância , Animais , Antígenos CD/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Temperatura , Fatores de Tempo , Trítio/metabolismoRESUMO
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.