RESUMEN
Orally administered ketoconazole may rarely induce liver injury and adrenal insufficiency. A metabolite formed by arylacetamide deacetylase (AADAC)-mediated hydrolysis has been observed in cellulo studies, and it is relevant to ketoconazole-induced cytotoxicity. This study tried to examine the significance of AADAC in ketoconazole-induced toxicity in vivo using Aadac knockout mice. Oral administration of 150 mg/kg ketoconazole resulted in the area under the plasma concentration-time curve values of ketoconazole and N-deacetylketoconazole, a hydrolyzed metabolite of ketoconazole, in Aadac knockout mice being significantly higher and lower than those in wild-type mice, respectively. With the administration of ketoconazole (300 mg/kg/day) for 7 days, Aadac knockout mice showed higher mortality (100%) than wild-type mice (42.9%), and they also showed significantly higher plasma alanine transaminase and lower corticosterone levels, thus representing liver injury and steroidogenesis inhibition, respectively. It was suggested that a higher plasma ketoconazole concentration likely accounts for the inhibition of the synthesis of corticosterone, which has anti-inflammatory effects, in the adrenal gland in Aadac KO mice. In Aadac knockout mice, hepatic mRNA levels of immune- and inflammation-related factors were increased by the administration of 300 mg/kg ketoconazole, and the increase was restored by the replenishment of corticosterone (40 mg/kg, s.c.) along with recoveries of plasma alanine transaminase levels. In conclusion, Aadac defects exacerbate ketoconazole-induced liver injury by inhibiting glucocorticoid synthesis and enhancing the inflammatory response. This in vivo study revealed that the hydrolysis of ketoconazole by AADAC can mitigate ketoconazole-induced toxicities.
Asunto(s)
Insuficiencia Suprarrenal/genética , Hidrolasas de Éster Carboxílico/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Cetoconazol/toxicidad , Insuficiencia Suprarrenal/enzimología , Insuficiencia Suprarrenal/etiología , Animales , Área Bajo la Curva , Hidrolasas de Éster Carboxílico/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Regulación Enzimológica de la Expresión Génica , Hidrólisis , Cetoconazol/metabolismo , Cetoconazol/farmacocinética , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Euodiae Fructus (EF), the dried unripe scented fruit of Euodia rutaecarpa (Juss.) Benth., was reported to show anti-hypertensive, antitumor, and anti-obesity effects. The main alkaloids of EF were reported as the reason for toxicity of EF by metabolic activation majority through CYP3A. Up till the present moment, the cytotoxicity mechanisms of EF have not yet to be fully clarified. For the purposes of this article, the influence of CYP3A inducer and inhibitor on cytotoxicity of EF and metabolism in L02 cells of five alkaloids related to toxicity of EF were evaluated. The results indicated that CYP3A inducer aggravated the toxicity and CYP3A inhibitor alleviated the toxicity. UPLC-Q-Exactive-MS was used for the identification of five alkaloids of EF in L02 cells. A total of 13 metabolites were detected in L02 cells. In general, five alkaloids were widely metabolized in L02 cells such as oxygenation, demethylation, dehydrogenation, and etc. In addition, oxygenation was the main metabolic pathway. It was inferred that the toxicity of EF was closely related to the CYP3A and the metabolic intermediate might be one of the reasons for the toxicity of EF. Hence, the choice of optimal dose might be critical to avoid the adverse reactions owing to combination of EF and CYP3A inducer.
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Alcaloides/química , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Medicamentos Herbarios Chinos/toxicidad , Evodia/toxicidad , Hígado/efectos de los fármacos , Alcaloides/metabolismo , Alcaloides/toxicidad , Línea Celular , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Evodia/química , Evodia/metabolismo , Frutas/química , Frutas/metabolismo , Frutas/toxicidad , Humanos , Hígado/enzimología , Espectrometría de MasasRESUMEN
This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HT7R ligand with antidepressant activity on mice. The combination of DFT calculations of 1H NMR chemical shifts with docking and dynamic simulations, in comparison to experimental screening results, provided prediction of the configuration for one of two present stereogenic centers. The experimental data for stereoisomers (MF-8A-MF-8D) confirmed the significant impact of stereochemistry on both, 5-HT7R affinity and antagonistic action, with Ki and Kb values in the range of 3-366 nM and 0.024-99 µM, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycoprotein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities.
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Hidantoínas/farmacocinética , Piperazinas/farmacocinética , Antagonistas de la Serotonina/farmacocinética , Animales , Sitios de Unión , Línea Celular Tumoral , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Inhibidores del Citocromo P-450 CYP3A/síntesis química , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Teoría Funcional de la Densidad , Estabilidad de Medicamentos , Humanos , Hidantoínas/síntesis química , Hidantoínas/metabolismo , Hidantoínas/toxicidad , Ratones , Microsomas Hepáticos/metabolismo , Modelos Químicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piperazinas/síntesis química , Piperazinas/metabolismo , Piperazinas/toxicidad , Unión Proteica , Espectroscopía de Protones por Resonancia Magnética , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/toxicidad , EstereoisomerismoAsunto(s)
Antivirales/toxicidad , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/toxicidad , Neumonía Viral/tratamiento farmacológico , Enfermedades de la Retina/inducido químicamente , Epitelio Pigmentado de la Retina/efectos de los fármacos , Ritonavir/toxicidad , Antirreumáticos/toxicidad , COVID-19 , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Sinergismo Farmacológico , Humanos , Pandemias , SARS-CoV-2RESUMEN
PURPOSE: Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life. PATIENTS AND METHODS: This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity. RESULTS: Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors). CONCLUSION: P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Pirimidinas/toxicidad , Sulfonamidas/toxicidad , Sunitinib/toxicidad , Anciano , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Indazoles , Masculino , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Estudios Retrospectivos , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sunitinib/administración & dosificación , Sunitinib/farmacocinéticaRESUMEN
The incubation system of CYP2E1 and CYP3A4 enzymes in rat liver microsomes was established to investigate the effects of psoralidin, isobavachalcone, neobavaisoflavone and daidzein from Fructus Psoraleae in vitro. The relevant metabolites were measured by the method of high performance liquid chromatography (HPLC), after probe substrates of 4-nitrophenol, testosterone and the drugs at different concentrations were added to the incubation systems. In addition, real-time RT-PCR was performed to determine the effect of psoralidin, neobavaisoflavone and daidzein on the mRNA expression of CYP3A4 in rat liver. The results suggested that psoralidin, isobavachalcone and neobavaisoflavone were Medium-intensity inhibitors of CYP2E1 with Ki values of 2.58, 1.28 and 19.07 µM, respectively, which could inhibit the increase of CYP2E1 and reduce diseases caused by lipid peroxidation. Isobavachalcone (Ki = 37.52 µM) showed a weak competitive inhibition on CYP3A4. Psoralidin and neobavaisoflavone showed obvious induction effects on CYP3A4 in the expression level of mRNA, which could accelerate the effects of drug metabolism and lead to the risk of inducing DDIs and serious adverse reactions. The results could be used for guideline of Fructus Psoraleae in clinic, which aimed to calculate the drug toxicity by studying the drug-drug interactions caused by the induction and inhibition of CYP450.
Asunto(s)
Benzofuranos/toxicidad , Chalconas/toxicidad , Cumarinas/toxicidad , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Isoflavonas/toxicidad , Microsomas Hepáticos/metabolismo , Animales , Benzofuranos/metabolismo , Chalconas/metabolismo , Cumarinas/metabolismo , Inhibidores del Citocromo P-450 CYP2E1/metabolismo , Inhibidores del Citocromo P-450 CYP2E1/toxicidad , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Interacciones Farmacológicas , Isoflavonas/metabolismo , Ratas Sprague-DawleyRESUMEN
1,3,8-Trihydroxy-6-methylanthraquinone (emodin), a widely existing natural product in herbal medicines, has been reported to be hepatotoxic, but the exact underlying mechanism is still not fully understood. The objective of the present study was to evaluate the role of CYP3A and glutathione (GSH) in emodin-induced liver injury. Primary human hepatocytes were exposed to emodin with and without addition of CYP3A inducer/inhibitor and GSH synthesis inhibitor. It was found that emodin-mediated cytotoxicity increased when CYP3A was activated and GSH was depleted. Hepatotoxicity induced by emodin in rats by activation/inhibition of CYP3A and depletion of GSH was further investigated. Administration of emodin in combination with l-buthionine sulfoximine (BSO) or dexamethasone (DEX) resulted in aggravated liver injury, whereas pretreatment with ketoconazole (KTZ) suppressed the side effects caused by emodin. In addition, plasma exposure of emodin and its glucuronide metabolite were measured by ultraperformance liquid chromatography triple quadrupole mass spectrometry. Emodin and its glucuronide were lower in BSO-, DEX-, and KTZ- co-treated rats compared with those administered with emodin alone. In conclusion, these mentioned results suggested that CYP3A induction and GSH depletion might be involved in hepatotoxicity induced by emodin. This study may help to understand the risk factors and the mechanism of hepatotoxicity of emodin in humans.
Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Emodina/toxicidad , Glutatión/metabolismo , Animales , Butionina Sulfoximina/toxicidad , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Dexametasona/toxicidad , Emodina/análisis , Emodina/metabolismo , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Masculino , Espectrometría de Masas , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Millions of people today use herbs either as food or in the form of medicine along with other medications. Many of the herbs can interact with these medications, causing either potentially dangerous side effects or improved or reduced benefits from the medication. OBJECTIVE: The present study was performed to determine the influence of cinnamon, on the pharmacokinetics and pharmacodynamics of pioglitazone. METHOD: Studies were conducted in normal and alloxan induced diabetic rats and rabbits with oral administration of selected doses of pioglitazone, cinnamon and their combination. Blood samples were collected at regular intervals of time and were analysed for glucose by GOD/POD method and for pioglitazone by HPLC method respectively. Body weights were also measured every week. RESULTS: Significant differences were seen in pharmacokinetic parameters of pioglitazone like AUC, t1/2, Ke, Cl/F, Vd/F when given in combination with cinnamon in normal and diabetic rabbits. The combination of pioglitazone and cinnamon was found to reduce the glucose levels and body weights significantly than pioglitazone. The results indicating increased AUC of pioglitazone on pretreatment with cinnamon suggest an interaction indicating decreased metabolism of pioglitazone as a result of CYP 3A4 inhibition and thereby producing a potentiating effect. CONCLUSION: Cinnamon enhanced the bioavailability of pioglitazone by inhibiting the CYP3A4 enzyme. Hence, cinnamon might be beneficial when used in combination with pioglitazone in diabetic patients and an adjustment of dose of pioglitazone may be necessary.
Asunto(s)
Glucemia/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP3A/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Interacciones de Hierba-Droga , Hipoglucemiantes/farmacocinética , Extractos Vegetales/farmacología , Tiazolidinedionas/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Biomarcadores/sangre , Glucemia/metabolismo , Cinnamomum/química , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/aislamiento & purificación , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Diabetes Mellitus Experimental/sangre , Hipoglucemiantes/administración & dosificación , Masculino , Pioglitazona , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Conejos , Ratas Sprague-Dawley , Tiazolidinedionas/administración & dosificación , Pérdida de Peso/efectos de los fármacosRESUMEN
(R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509, decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxyl-metabolite of VX-509, which is involved in clinically significant TDI-based DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.
Asunto(s)
Aldehído Oxidasa/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/metabolismo , Compuestos Heterocíclicos con 2 Anillos/farmacología , Inhibidores de las Cinasas Janus/farmacología , Hígado/enzimología , Microsomas Hepáticos/enzimología , Valina/análogos & derivados , Adulto , Anciano , Aldehído Oxidasa/metabolismo , Biotransformación , Células Cultivadas , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Hepatocitos/enzimología , Compuestos Heterocíclicos con 2 Anillos/metabolismo , Compuestos Heterocíclicos con 2 Anillos/toxicidad , Humanos , Hidroxilación , Inhibidores de las Cinasas Janus/metabolismo , Inhibidores de las Cinasas Janus/toxicidad , Cinética , Masculino , Persona de Mediana Edad , Medición de Riesgo , Valina/metabolismo , Valina/farmacología , Valina/toxicidad , Adulto JovenRESUMEN
BACKGROUND: Benzbromarone is a uricosuric drug in current clinical use that can cause serious hepatotoxicity. Chemically reactive and/or cytotoxic metabolites of benzbromarone have been identified; however there is a lack of available information on their role in benzbromarone hepatotoxicity. The reactive metabolites of some hepatotoxic drugs are known to covalently bind, or alternatively are targeted, to specific cytochrome P450 (P450) enzymes, a process that is often described as mechanism-based inhibition. OBJECTIVE: We examined whether benzbromarone causes a mechanism-based inhibition of human P450 enzymes. METHOD: Microsomes from human livers were preincubated with benzbromarone and NADPH, followed by evaluation of CYP2C9 and CYP3A4 activities. RESULTS: Benzbromarone metabolism resulted in inhibition of CYP3A4 but not CYP2C9 in a time-dependent manner. Confirmation of pseudo-first order kinetics of inhibition, a requirement for NADPH, and a lack of protection by scavengers suggested that benzbromarone is a mechanism-based CYP3A4 inhibitor. CONCLUSION: Modification of the P450 enzyme by the reactive metabolite is a common trait of drugs that induce idiosyncratic hepatotoxicity, and might provide a speculative, mechanistic model for the rare occurrences of this type of drug toxicity.
Asunto(s)
Benzbromarona/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/metabolismo , Microsomas Hepáticos/enzimología , Uricosúricos/farmacología , Benzbromarona/metabolismo , Benzbromarona/toxicidad , Biotransformación , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Humanos , Cinética , Modelos Biológicos , Uricosúricos/metabolismo , Uricosúricos/toxicidadRESUMEN
As is well-known, hERG plays an essential role in phase III repolarization of cardiac action potentials. Blocking of hERG channels can lead to LQTS. Inhibition of the metabolism of CYPs activities may elevate plasma levels, to further increase accumulation of drug on cardiac. The elevated serum levels may however elicit unexpected toxicities. Therefore, the inhibition tests of hERG and CYP are central to the preclinical studies because they may lead to severe cardiac toxicity. Berberine is widely used as an antibacterial agent and often combined with macrolides to treat gastropathy. Our objective was to assess cardiac toxicity during the combined use of Berberine with macrolides. (1) Azithromycin reduced hERG currents by accelerated channel inactivation. (2) The combination of Berberine with Azithromycin reduced hERG currents, producing an inhibitive effect stronger than use of a single drug alone, due to the high binding affinity for the onset of inactivation. (3) When cells were perfused concomitantly with Berberine and Clarithromycin, they showed a stronger inhibitive effect on hERG currents by decreasing the time constant for the onset of inactivation. (4) The combined administration of Berberine with Clarithromycin had a powerful inhibitive effect on CYP3A activities than use of a single drug alone. Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity.
Asunto(s)
Antibacterianos/toxicidad , Azitromicina/toxicidad , Berberina/toxicidad , Claritromicina/toxicidad , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Cardiopatías/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Bloqueadores de los Canales de Potasio/toxicidad , Animales , Citocromo P-450 CYP3A/metabolismo , Sinergismo Farmacológico , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/metabolismo , Células HEK293 , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Humanos , Masculino , Potenciales de la Membrana , Microsomas Hepáticos/enzimología , Miocitos Cardíacos/metabolismo , Ratas , Ratas Wistar , Medición de Riesgo , TransfecciónRESUMEN
Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.
Asunto(s)
Citocromo P-450 CYP3A/química , Inhibidores Enzimáticos/química , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Animales , Sitios de Unión , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Perros , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Femenino , Semivida , Humanos , Cinética , Células de Riñón Canino Madin Darby , Ratones , Ratones Desnudos , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Nicotinamida Fosforribosiltransferasa/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Pirimidinas/química , Pirimidinas/uso terapéutico , Pirimidinas/toxicidad , Solubilidad , Relación Estructura-Actividad , Termodinámica , Trasplante Heterólogo , Agua/químicaRESUMEN
Triptolide (TP) is an active component of Tripterygium wilfordii Hook. F and widely used to treat autoimmune and inflammatory diseases. It has been demonstrated that cytochrome P450 (CYP) are involved in the metabolism of TP. However, the underlying mechanisms of TP-induced toxicity mediated by hepatic CYP have not been well delineated. In this study, rat liver microsomes (RLM) and sandwich-cultured rat hepatocytes (SCRH) were used to identify the mechanism involving the CYP3A inhibition by TP and to evaluate TP-induced liver damage after CYP3A modulation by the known inhibitor, ketoconazole, and the known inducer, dexamethasone. The results showed that TP itself had a time- and concentration-dependent inhibitory effect on CYP3A. When the CYP3A inhibitor and inducer were added, the enzyme activity and hepatotoxicity changed significantly. The enzyme inducer increased CYP3A activity and decreased the metabolic half life (t1/2) of TP when compared to the control group, while the enzyme inhibitor had an opposite effect. Our findings reveal that TP is a weak CYP3A inhibitor involving the time-dependent inhibition mechanism. The induction or inhibition of CYP3A played an important role in TP-induced hepatotoxicity. Clinicians should be aware of the metabolic characteristics of TP to maximize therapeutic efficacy and reduce TP-induced toxicity.