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[PMID]:25870103
[Au] Autor:Iida A; Sasaki E; Yano A; Tsuneyama K; Fukami T; Nakajima M; Yokoi T
[Ad] Endereço:Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (A.I., E.S., A.Y., T.F., M.N., T.Y.); Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan (K.T.); and Depa
[Ti] Título:Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats.
[So] Source:Drug Metab Dispos;43(7):958-68, 2015 Jul.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Carbamazepine (CBZ) is widely used as an antiepileptic agent and causes rare but severe liver injury in humans. It has been generally recognized that reactive metabolites formed via the metabolic activation reaction contribute to the onset of liver injuries by several drugs. However, the role of CBZ metabolism in the development of liver injury is not fully understood. In this study, we developed a novel rat model of CBZ-induced liver injury and attempted to elucidate the associated mechanisms by focusing on the metabolism of CBZ. The repeated administration of CBZ for 5 days in combination with l-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, resulted in increases in the plasma alanine aminotransferase (ALT) levels and centrilobular necrosis in the liver that were observed in various degrees. The CBZ and 2-hydroxy-CBZ concentrations in the plasma after the last CBZ administration were lower in the rats with high plasma ALT levels compared with those with normal plasma ALT levels, showing the possibility that the further metabolism of CBZ and/or 2-hydroxy-CBZ is associated with the liver injury. Although a single administration of CBZ did not affect the plasma ALT levels, even when cotreated with BSO, pretreatment with dexamethasone, a CYP3A inducer, increased the plasma ALT levels. In addition, the rats cotreated with troleandomycin or ketoconazole, CYP3A inhibitors, suppressed the increased plasma ALT levels. In conclusion, reactive metabolite(s) of CBZ produced by CYP3A under the GSH-depleted condition might be involved in the development of liver injury in rats.
[Mh] Termos MeSH primário: Carbamazepina/metabolismo
Carbamazepina/toxicidade
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Citocromo P-450 CYP3A/metabolismo
Glutationa/metabolismo
[Mh] Termos MeSH secundário: Alanina Transaminase/metabolismo
Animais
Antibacterianos/farmacologia
Antifúngicos/farmacologia
Butionina Sulfoximina/farmacologia
Doença Hepática Induzida por Substâncias e Drogas/enzimologia
Indução Enzimática/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Glutationa/antagonistas & inibidores
Hidroxilação
Cetoconazol/farmacologia
Fígado/efeitos dos fármacos
Fígado/enzimologia
Fígado/metabolismo
Masculino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Ratos
Ratos Endogâmicos F344
Troleandomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antifungal Agents); 0 (Enzyme Inhibitors); 33CM23913M (Carbamazepine); 5072-26-4 (Buthionine Sulfoximine); C4DZ64560D (Troleandomycin); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 2.6.1.2 (Alanine Transaminase); GAN16C9B8O (Glutathione); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150415
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.115.063370


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[PMID]:25451576
[Au] Autor:Shen Q; Zuo M; Ma L; Tian Y; Wang L; Jiang H; Zhou Q; Zhou H; Yu L; Zeng S
[Ad] Endereço:Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
[Ti] Título:Demethylation of neferine in human liver microsomes and formation of quinone methide metabolites mediated by CYP3A4 accentuates its cytotoxicity.
[So] Source:Chem Biol Interact;224:89-99, 2014 Dec 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Neferine is a bisbenzylisoquinoline alkaloid isolated from the seed embryos of Nelumbonucifera Gaertn (Lotus) with various potent pharmacological effects. Recently, neferine has attracted attention for its anti-tumor activities. Our study explored its metabolism and cytotoxicity mechanism. Approaches using chemical inhibitors and recombinant human enzymes to characterize the involved enzymes and kinetic studies indicated that the demethylation of neferine by cytochrome P450 (CYP) 2D6 and CYP3A4 fitted a biphasic kinetic profile. Glutathione (GSH) was used as a trapping agent to identify reactive metabolites of neferine, and four novel GSH conjugates were detected with [M+H](+) ions at m/z 902.4, 916.2, 916.1, and 930.4. Based on its structure containing para-methylene phenol and results from a product ion scan, GSH tends to conjugate with C9' after undergoing oxidative metabolism to form the binding site predominated by CYP3A4. Furthermore, the addition of recombinant human GSTA1, GSTT1, and GSTP1 had little effect on the production of the GSH conjugates. In a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay, combined with the GSH modulators l-buthionine sulfoximine or N-acetyl-l-cysteine, neferine treatment of MDCK-hCYP3A4 and HepG2 cells revealed that CYP3A4 expression and cellular GSH content could cause an EC50 shift. Metabolic activation mediated by CYP3A4 and GSH depletion significantly enhanced neferine-induced cytotoxicity.
[Mh] Termos MeSH primário: Antineoplásicos/metabolismo
Benzilisoquinolinas/metabolismo
Citocromo P-450 CYP3A/metabolismo
Indolquinonas/metabolismo
Microssomos Hepáticos/metabolismo
[Mh] Termos MeSH secundário: Acetilcisteína/farmacologia
Animais
Antineoplásicos/farmacocinética
Antineoplásicos/farmacologia
Benzilisoquinolinas/farmacocinética
Benzilisoquinolinas/farmacologia
Butionina Sulfoximina/farmacologia
Citocromo P-450 CYP2C8/metabolismo
Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP3A/farmacologia
Cães
Glutationa/metabolismo
Células Hep G2
Seres Humanos
Cetoconazol/farmacologia
Cinética
Células Madin Darby de Rim Canino
Troleandomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzylisoquinolines); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Indolequinones); 138230-21-4 (quinone methide); 2292-16-2 (neferine); 5072-26-4 (Buthionine Sulfoximine); C4DZ64560D (Troleandomycin); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); EC 1.14.14.1 (Cytochrome P-450 CYP3A); GAN16C9B8O (Glutathione); R9400W927I (Ketoconazole); WYQ7N0BPYC (Acetylcysteine)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170213
[Lr] Data última revisão:
170213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


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[PMID]:23732297
[Au] Autor:Grimsley A; Gallagher R; Hutchison M; Pickup K; Wilson ID; Samuelsson K
[Ad] Endereço:Global DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield SK10 4TG, United Kingdom.
[Ti] Título:Drug-drug interactions and metabolism in cytochrome P450 2C knockout mice: application to troleandomycin and midazolam.
[So] Source:Biochem Pharmacol;86(4):529-38, 2013 Aug 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Drug-drug interactions (DDIs) may cause serious drug toxicity and delay development of candidate drugs. Screening using human liver microsomes and hepatocytes can help predict DDIs but do not always provide the degree of certainty required for confident progression of a candidate drug. Thus a suitable in vivo test system could be of great value. Here a Cyp2c knockout (KO) mouse was investigated for studying DDIs using midazolam (MDZ) a standard human CYP3A4 substrate and troleandomycin (TAO) a potent human CYP3A4 inhibitor. Pharmacokinetics (PK) and biotransformation of MDZ were investigated following dosing to Cyp2c KO and wild type mice before and after TAO treatment. The noteworthy differences in the metabolism of MDZ in Cyp2c KO compared to wild type mice confirms the important role that Cyp2c enzymes play in the murine metabolism of MDZ in vivo. The impact of Cyp3a inhibition produced a further increase in circulating MDZ concentrations in all individuals from both strains of mice though the impact of the elimination of the Cyp2c pathway in the KO mice on the AUC was less than perhaps expected. We have shown that TAO produces an increase in the MDZ concentration and a reduction in the 1'hydroxymidazolam/midazolam formation ratio but the expected difference in the magnitude of this effect between the wild type and the Cyp2c KO mice was not seen. The magnitude of the TAO effect was also smaller than is reported in humans. Hence further work is required before this animal model could be used to predict clinical interactions.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/metabolismo
Midazolam/farmacocinética
Troleandomicina/farmacologia
[Mh] Termos MeSH secundário: Animais
Bile/metabolismo
Biotransformação
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A
Sistema Enzimático do Citocromo P-450/genética
Interações Medicamentosas
Camundongos
Camundongos Knockout
Midazolam/análogos & derivados
Midazolam/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (cytochrome P-450 CYP2C subfamily); 9035-51-2 (Cytochrome P-450 Enzyme System); C4DZ64560D (Troleandomycin); E5142BN92Z (1-hydroxymethylmidazolam); EC 1.14.14.1 (Cytochrome P-450 CYP3A); R60L0SM5BC (Midazolam)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130605
[St] Status:MEDLINE


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[PMID]:23698259
[Au] Autor:Misaka S; Kawabe K; Onoue S; Werba JP; Giroli M; Watanabe H; Yamada S
[Ad] Endereço:Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka.
[Ti] Título:Green tea extract affects the cytochrome P450 3A activity and pharmacokinetics of simvastatin in rats.
[So] Source:Drug Metab Pharmacokinet;28(6):514-8, 2013.
[Is] ISSN:1880-0920
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Effects of green tea extract (GTE) on the activity of cytochrome P450 (CYP) enzymes and pharmacokinetics of simvastatin (SIM) were investigated in rats. Inhibitory effects of GTE on CYP3A activity were investigated in rat hepatic microsomes (RHM) using midazolam (MDZ) 1'-hydroxylation as a probe reaction. SD female rats received a single oral dose of GTE (400 mg/kg) or troleandomycin (TAO, a CYP3A selective inhibitor, 500 mg/kg), followed 30 min later by SIM (20 mg/kg). Plasma concentrations of SIM and its active metabolite, simvastatin acid, were determined up to 6 h after the SIM administration using LC/MS/MS. In RHM, GTE inhibited MDZ 1'-hydroxylation with IC50 and K(i)(app) values of 12.5 and 18.8 µg/mL, respectively, in a noncompetitive manner. Area under plasma concentration-time curves for SIM in the GTE and TAO groups were increased by 3.4- and 10.2-fold, respectively, compared with the control. The maximum concentrations of SIM were higher in the GTE (3.3-fold) and TAO (9.5-fold) groups. GTE alters the pharmacokinetics of SIM, probably by inhibiting intestinal CYP3A.
[Mh] Termos MeSH primário: Camellia sinensis/química
Citocromo P-450 CYP3A/metabolismo
Extratos Vegetais/farmacologia
Sinvastatina/farmacocinética
[Mh] Termos MeSH secundário: Animais
Inibidores do Citocromo P-450 CYP3A
Feminino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
Midazolam/metabolismo
Ratos
Troleandomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Plant Extracts); AGG2FN16EV (Simvastatin); C4DZ64560D (Troleandomycin); EC 1.14.14.1 (Cytochrome P-450 CYP3A); R60L0SM5BC (Midazolam)
[Em] Mês de entrada:1409
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130524
[St] Status:MEDLINE


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[PMID]:23353841
[Au] Autor:Martinkova M; Kubickova B; Stiborova M
[Ad] Endereço:Department of Biochemistry, Charles University, Prague, Czech Republic.
[Ti] Título:Effects of cytochrome P450 inhibitors on peroxidase activity.
[So] Source:Neuro Endocrinol Lett;33 Suppl 3:33-40, 2012.
[Is] ISSN:0172-780X
[Cp] País de publicação:Sweden
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Of several enzymes metabolizing xenobiotics, cytochrome P450 (CYP) and peroxidase enzymes seem to be most important. One of the major challenges in studies investigating metabolism of xenobiotics is to resolve which of these two groups of enzymes is predominant to metabolize individual xenobiotic compounds. Utilization of selective inhibitors of CYP and peroxidase enzymes might be a useful tool to identify the contribution of these enzymes to metabolism of xenobiotics in samples, where both types of enzymes are present. The aim of this study was to investigate specificities of several known CYP inhibitors to these enzymes; whether they inhibit only the CYP enzymes and do not inhibit peroxidases. METHODS: Since the oxidation of o-anisidine catalyzed by a model peroxidase used, horseradish peroxidase (HRP), is a two-substrate reaction, the inhibition potential of tested chemicals was studied with respect to both peroxidase substrates, o-anisidine and hydrogen peroxide. Initial velocities of o-anisidine oxidation by HRP under various conditions were determined spectrophotometrically. RESULTS: The CYP inhibitors metyrapone, troleandomycine, disulfiram, sulfaphenazole, quinidine and 1-aminobenzotriazole do not inhibit o-anisidine oxidation catalyzed by HRP. In contrast, ketoconazole, diethyldithiocarbamate, ellipticine, α-naphtoflavone, proadifen SKF525A, piperonylbutoxide, were found to inhibit not only the CYPs, but also the HRP-mediated oxidation of o-anisidine. Interestingly, α-naphtoflavone inhibits oxidation of o-anisidine by HRP with respect to H2O2, but not with respect to o-anisidine. Diethyldithiocarbamate is the most potent peroxidase inhibitor of o-anisidine oxidation with Ki with respect to o-anisidine of 10 µM and Ki with respect to H2O2 of 60 µM, being even the better peroxidase inhibitor than the classical "peroxidase inhibitor" - propyl gallate (Ki with respect to o-anisidine of 60 µM and Ki with respect to H2O2 of 750 µM). CONCLUSIONS: The results of the present study demonstrate that 1-aminobenzotriazole, a potent inhibitor of various CYP enzymes, seems to be the best candidate suitable for utilization in studies evaluating participation of CYP enzymes in metabolism of xenobiotics in various complex biological materials containing both CYP and peroxidase enzymes. Moreover, precaution to prevent misinterpretation of results is necessary in cases when proadifen SKF525A, piperonylbutoxide, diethyldithiocarbamate, ketoconazole, α-naphtoflavone and ellipticine are used in similar studies (as CYP inhibitors in various complex biological materials containing both CYP and peroxidase enzymes), since these chemicals can except of CYP enzymes inhibit also peroxidase-mediated reactions.
[Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450
Inibidores Enzimáticos/farmacologia
Peroxidase do Rábano Silvestre/antagonistas & inibidores
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Benzoflavonas/química
Benzoflavonas/farmacologia
Dissulfiram/química
Dissulfiram/farmacologia
Ditiocarb/química
Ditiocarb/farmacologia
Elipticinas/química
Elipticinas/farmacologia
Ativação Enzimática/efeitos dos fármacos
Inibidores Enzimáticos/química
Peroxidase do Rábano Silvestre/metabolismo
Seres Humanos
Cetoconazol/química
Cetoconazol/farmacologia
Metirapona/química
Metirapona/farmacologia
Butóxido de Piperonila/química
Butóxido de Piperonila/farmacologia
Proadifeno/química
Proadifeno/farmacologia
Quinidina/química
Quinidina/farmacologia
Relação Estrutura-Atividade
Especificidade por Substrato/efeitos dos fármacos
Sulfafenazol/química
Sulfafenazol/farmacologia
Triazóis/química
Troleandomicina/química
Troleandomicina/farmacologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Ellipticines); 0 (Enzyme Inhibitors); 0 (Triazoles); 0J8L4V3F81 (Sulfaphenazole); 117VLW7484 (ellipticine); 1614-12-6 (1-aminobenzotriazole); 604-59-1 (alpha-naphthoflavone); 99Z2744345 (Ditiocarb); A510CA4CBT (Proadifen); C4DZ64560D (Troleandomycin); EC 1.11.1.- (Horseradish Peroxidase); ITX08688JL (Quinidine); LWK91TU9AH (Piperonyl Butoxide); R9400W927I (Ketoconazole); TR3MLJ1UAI (Disulfiram); ZS9KD92H6V (Metyrapone)
[Em] Mês de entrada:1304
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130129
[St] Status:MEDLINE


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[PMID]:22490230
[Au] Autor:Albaugh DR; Fullenwider CL; Fisher MB; Hutzler JM
[Ad] Endereço:Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry (Drug Metabolism and Pharmacokinetics), 175 Briar Ridge Road, R&D 10574, Ridgefield, CT 06877, USA. daniel.albaugh@Boehringer-Ingelheim.com
[Ti] Título:Time-dependent inhibition and estimation of CYP3A clinical pharmacokinetic drug-drug interactions using plated human cell systems.
[So] Source:Drug Metab Dispos;40(7):1336-44, 2012 Jul.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The current studies assessed the utility of freshly plated hepatocytes, cryopreserved plated hepatocytes, and cryopreserved plated HepaRG cells for the estimation of inactivation parameters k(inact) and K(I) for CYP3A. This was achieved using a subset of CYP3A time-dependent inhibitors (fluoxetine, verapamil, clarithromycin, troleandomycin, and mibefradil) representing a range of potencies. The estimated k(inact) and K(I) values for each time-dependent inhibitor were compared with those obtained using human liver microsomes and used to estimate the magnitude of clinical pharmacokinetic drug-drug interaction (DDI). The inactivation kinetic parameter, k(inact), was most consistent across systems tested for clarithromycin, verapamil, and troleandomycin, with a high k(inact) of 0.91 min(-1) observed for mibefradil in HepaRG cells. The apparent K(I) estimates derived from the various systems displayed a range of variability from 3-fold for clarithromycin (5.4-17.7 µM) to 6-fold for verapamil (1.9-12.6 µM). In general, the inactivation kinetic parameters derived from the cell systems tested fairly replicated what was observed in time-dependent inhibition studies using human liver microsomes. Despite some of the observed differences in inactivation kinetic parameters, the estimated DDIs derived from each of the tested systems generally agreed with the clinically reported DDI within approximately 2-fold. In addition, a plated cell approach offered the ability to conduct longer primary incubations (greater than 30 min), which afforded improved ability to identify the weak time-dependent inhibitor fluoxetine. Overall, results from these studies suggest that in vitro inactivation parameters generated from plated cell systems may be a practical approach for identifying time-dependent inhibitors and for estimating the magnitude of clinical DDIs.
[Mh] Termos MeSH primário: Claritromicina/farmacologia
Inibidores do Citocromo P-450 CYP3A
Citocromo P-450 CYP3A/metabolismo
Hepatócitos/metabolismo
Microssomos Hepáticos/metabolismo
Troleandomicina/farmacologia
Verapamil/farmacologia
[Mh] Termos MeSH secundário: Células Cultivadas
Claritromicina/farmacocinética
Criopreservação/métodos
Interações Medicamentosas
Hepatócitos/efeitos dos fármacos
Seres Humanos
Cinética
Microssomos Hepáticos/efeitos dos fármacos
Troleandomicina/farmacocinética
Verapamil/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); C4DZ64560D (Troleandomycin); CJ0O37KU29 (Verapamil); EC 1.14.14.1 (CYP3A protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); H1250JIK0A (Clarithromycin)
[Em] Mês de entrada:1301
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120412
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.112.044644


  7 / 446 MEDLINE  
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[PMID]:22416982
[Au] Autor:Choi YH; Lee MG
[Ad] Endereço:College of Pharmacy, Dongguk University-Seoul, Seoul, South Korea.
[Ti] Título:Pharmacokinetic and pharmacodynamic interaction between nifedipine and metformin in rats: competitive inhibition for metabolism of nifedipine and metformin by each other via CYP isozymes.
[So] Source:Xenobiotica;42(5):483-95, 2012 May.
[Is] ISSN:1366-5928
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It has been reported that hypertension exponentially increases in the patients with type 2 diabetes mellitus. Thus, this study was performed to investigate the pharmacokinetic and pharmacodynamic interactions between nifedipine and metformin, since both drugs were commonly metabolized via hepatic CYP2C and 3A subfamilies in rats. Nifedipine (3 mg/kg) and metformin (100 mg/kg) were simultaneously administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V(max)), Michaelis-Menten constant (K(m)), and intrinsic clearance (CL(int)) for the disappearance of each drug, apparent inhibition constant (K(i)) and [I]/K(i) ratios of each drug in liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs and blood pressure were also measured. After the simultaneous single intravenous administration of both drugs together, the AUCs of each drug were significantly greater than that in each drug alone due to the competitive inhibition for the metabolism of nifedipine by metformin via hepatic CYP3A1/2 and of metformin by nifedipine via hepatic CYP2C6 and 3A1/2. After the simultaneous single oral administration of both drugs, the significantly greater AUCs of each drug than that in each drug alone could have mainly been due to the competitive inhibition for the metabolism of nifedipine and metformin by each other via intestinal CYP3A1/2 in addition to competitive inhibition for the hepatic metabolism of each drug as same as the intravenous study.
[Mh] Termos MeSH primário: Citocromo P-450 CYP3A/metabolismo
Metformina/farmacologia
Metformina/farmacocinética
Nifedipino/farmacologia
Nifedipino/farmacocinética
[Mh] Termos MeSH secundário: Administração Oral
Animais
Baculoviridae/efeitos dos fármacos
Baculoviridae/metabolismo
Proteínas Sanguíneas/metabolismo
Linhagem Celular
Dexametasona/farmacologia
Interações Medicamentosas
Seres Humanos
Injeções Intravenosas
Intestinos/efeitos dos fármacos
Intestinos/metabolismo
Isoenzimas/metabolismo
Cinética
Masculino
Metformina/administração & dosagem
Metformina/metabolismo
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Nifedipino/administração & dosagem
Nifedipino/metabolismo
Ligação Proteica/efeitos dos fármacos
Quinina/farmacologia
Ratos
Ratos Sprague-Dawley
Sulfafenazol/farmacologia
Troleandomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Proteins); 0 (Isoenzymes); 0J8L4V3F81 (Sulfaphenazole); 7S5I7G3JQL (Dexamethasone); 9100L32L2N (Metformin); A7V27PHC7A (Quinine); C4DZ64560D (Troleandomycin); EC 1.14.14.1 (Cytochrome P-450 CYP3A); I9ZF7L6G2L (Nifedipine)
[Em] Mês de entrada:1209
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120316
[St] Status:MEDLINE
[do] DOI:10.3109/00498254.2011.633177


  8 / 446 MEDLINE  
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[PMID]:21835977
[Au] Autor:Chen Y; Liu L; Monshouwer M; Fretland AJ
[Ad] Endereço:Department of Drug Metabolism and Pharmacokinetics, Roche-Palo Alto, LLC, California, USA.
[Ti] Título:Determination of time-dependent inactivation of CYP3A4 in cryopreserved human hepatocytes and assessment of human drug-drug interactions.
[So] Source:Drug Metab Dispos;39(11):2085-92, 2011 Nov.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Assessment of time-dependent inhibition (TDI), especially CYP3A4, is an important parameter for preclinical and clinical development. The use of human liver microsomes (HLM) is the most common in vitro matrix to assess TDI, but this often leads to an overprediction of an actual effect observed clinically. Recently, the use of human hepatocytes has been hypothesized as a more relevant and possibly predictive matrix for the assessment of CYP3A4 TDI. Our work evaluates and optimizes three different human hepatocyte assays for the assessment of CYP3A4 TDI using pooled cryopreserved human hepatocytes. Using two of the optimized methods, the time-dependent inhibition kinetic parameters (K(I) and k(inact)) for four known CYP3A4 TDI (diltiazem, erythromycin, verapamil, and troleandomycin) were determined. When comparing TDI in HLM, the K(I) values from hepatocytes were in general 4- to 13-fold higher than that in HLM, whereas the k(inact) values in human hepatocytes were similar or slightly higher or lower depending on the inhibitor. The inactivation potency (k(inact)/K(I)) for four tested CYP3A4 inactivators in human hepatocytes was generally lower than that in HLM due to either lower affinity (K(I)) or lower inactivation rate (k(inact)) or both. When drug interactions were simulated with Simcyp using either HLM or human hepatocyte data, the predictions using the kinetic parameters from human hepatocytes resulted in a much better simulated change in pharmacokinetics compared with observed clinical data.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP3A
Citocromo P-450 CYP3A/metabolismo
Inibidores Enzimáticos/farmacologia
Hepatócitos/efeitos dos fármacos
Hepatócitos/enzimologia
[Mh] Termos MeSH secundário: Criopreservação
Diltiazem/farmacologia
Interações Medicamentosas
Ativação Enzimática/efeitos dos fármacos
Eritromicina/farmacologia
Seres Humanos
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
Farmacocinética
Medição de Risco/métodos
Fatores de Tempo
Troleandomicina/farmacologia
Verapamil/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Enzyme Inhibitors); 63937KV33D (Erythromycin); C4DZ64560D (Troleandomycin); CJ0O37KU29 (Verapamil); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EE92BBP03H (Diltiazem)
[Em] Mês de entrada:1205
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110813
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.111.040634


  9 / 446 MEDLINE  
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[PMID]:21766881
[Au] Autor:Amunom I; Dieter LJ; Tamasi V; Cai J; Conklin DJ; Srivastava S; Martin MV; Guengerich FP; Prough RA
[Ad] Endereço:Department of Biochemistry and Molecular Biology, The University of Louisville School of Medicine , Louisville, KY 40292, USA.
[Ti] Título:Cytochromes P450 catalyze the reduction of α,ß-unsaturated aldehydes.
[So] Source:Chem Res Toxicol;24(8):1223-30, 2011 Aug 15.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The metabolism of α,ß-unsaturated aldehydes, e.g., 4-hydroxynonenal, involves oxidation to carboxylic acids, reduction to alcohols, and glutathionylation to eventually form mercapturide conjugates. Recently, we demonstrated that P450s can oxidize aldehydes to carboxylic acids, a reaction previously thought to involve aldehyde dehydrogenase. When recombinant cytochrome P450 3A4 was incubated with 4-hydroxynonenal, O(2), and NADPH, several products were produced, including 1,4-dihydroxynonene (DHN), 4-hydroxy-2-nonenoic acid (HNA), and an unknown metabolite. Several P450s catalyzed the reduction reaction in the order (human) P450 2B6 ≅ P450 3A4 > P450 1A2 > P450 2J2 > (mouse) P450 2c29. Other P450s did not catalyze the reduction reaction (human P450 2E1 and rabbit P450 2B4). Metabolism by isolated rat hepatocytes showed that HNA formation was inhibited by cyanamide, while DHN formation was not affected. Troleandomycin increased HNA production 1.6-fold while inhibiting DHN formation, suggesting that P450 3A11 is a major enzyme involved in rat hepatic clearance of 4-HNE. A fluorescent assay was developed using 9-anthracenealdehyde to measure both reactions. Feeding mice a diet containing t-butylated hydroxyanisole increased the level of both activities with hepatic microsomal fractions but not proportionally. Miconazole (0.5 mM) was a potent inhibitor of these microsomal reduction reactions, while phenytoin and α-naphthoflavone (both at 0.5 mM) were partial inhibitors, suggesting the role of multiple P450 enzymes. The oxidative metabolism of these aldehydes was inhibited >90% in an Ar or CO atmosphere, while the reductive reactions were not greatly affected. These results suggest that P450s are significant catalysts of the reduction of α,ß-unsaturated aldehydes in the liver.
[Mh] Termos MeSH primário: Aldeídos/metabolismo
Citocromo P-450 CYP3A/metabolismo
[Mh] Termos MeSH secundário: Aldeídos/química
Animais
Antracenos/química
Antracenos/metabolismo
Biocatálise
Células Cultivadas
Cianamida/farmacologia
Citocromo P-450 CYP3A/genética
Hepatócitos/efeitos dos fármacos
Seres Humanos
Hidroxiácidos/química
Hidroxiácidos/metabolismo
Masculino
Camundongos
Microssomos Hepáticos/metabolismo
NADP/metabolismo
Oxirredução
Oxigênio/metabolismo
Ratos
Ratos Sprague-Dawley
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Troleandomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (4-hydroxy-2-nonenoic acid); 0 (Aldehydes); 0 (Anthracenes); 0 (Hydroxy Acids); 0 (Recombinant Proteins); 420-04-2 (Cyanamide); 53-59-8 (NADP); 642-31-9 (9-anthraldehyde); C4DZ64560D (Troleandomycin); EC 1.14.14.1 (Cytochrome P-450 CYP3A); K1CVM13F96 (4-hydroxy-2-nonenal); S88TT14065 (Oxygen)
[Em] Mês de entrada:1112
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110720
[St] Status:MEDLINE
[do] DOI:10.1021/tx200080b


  10 / 446 MEDLINE  
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[PMID]:21576599
[Au] Autor:Honda A; Miyazaki T; Ikegami T; Iwamoto J; Maeda T; Hirayama T; Saito Y; Teramoto T; Matsuzaki Y
[Ad] Endereço:Department of Gastroenterology, Center for Collaborative Research, Ibaraki 300-0395, Japan.
[Ti] Título:Cholesterol 25-hydroxylation activity of CYP3A.
[So] Source:J Lipid Res;52(8):1509-16, 2011 Aug.
[Is] ISSN:1539-7262
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To date, many studies have been conducted using 25-hydroxycholesterol, which is a potent regulator of lipid metabolism. However, the origins of this oxysterol have not been entirely elucidated. Cholesterol 25-hydroxylase is one of the enzymes responsible for the metabolism of 25-hydroxycholesterol, but the expression of this enzyme is very low in humans. This oxysterol is also synthesized by sterol 27-hydroxylase (CYP27A1) and cholesterol 24-hydroxylase(CYP46A1), but it is only a minor product of these enzymes. We now report that CYP3A synthesizes a significant amount of 25-hydroxycholesterol and may participate in the regulation of lipid metabolism. Induction of CYP3A by pregnenolone-16α-carbonitrile caused the accumulation of 25-hydroxycholesterol in a cell line derived from mouse liver. Furthermore, treatment of the cells with troleandomycin, a specific inhibitor of CYP3A, significantly reduced cellular 25-hydroxycholesterol concentrations. In cells that overexpressed human recombinant CYP3A4, the activity of cholesterol 25-hydroxylation was found to be higher than that of cholesterol 4ß-hydroxylation, a known marker activity of CYP3A4. In addition, 25-hydroxycholesterol concentrations in normal human sera correlated positively with the levels of 4ß-hydroxycholesterol (r = 0.650, P < 0.0001, n = 78), but did not significantly correlate with the levels of 27-hydroxycholesterol or 24S-hydroxycholesterol. These results demonstrate the significance of CYP3A on the production of 25-hydroxycholesterol.
[Mh] Termos MeSH primário: Citocromo P-450 CYP3A/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Ativação Enzimática/efeitos dos fármacos
Hepatócitos/enzimologia
Hidroxicolesteróis/metabolismo
Metabolismo dos Lipídeos/fisiologia
Fígado/enzimologia
[Mh] Termos MeSH secundário: Animais
Western Blotting
Linhagem Celular
Citocromo P-450 CYP3A/genética
Inibidores das Enzimas do Citocromo P-450
Eletroforese em Gel de Poliacrilamida
Expressão Gênica
Hepatócitos/citologia
Seres Humanos
Fígado/citologia
Camundongos
Reação em Cadeia da Polimerase
Carbonitrila de Pregnenolona/farmacologia
RNA Mensageiro/análise
RNA Mensageiro/biossíntese
Esteroide Hidroxilases
Troleandomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Hydroxycholesterols); 0 (RNA, Messenger); 1434-54-4 (Pregnenolone Carbonitrile); 767JTD2N31 (25-hydroxycholesterol); 9035-51-2 (Cytochrome P-450 Enzyme System); C4DZ64560D (Troleandomycin); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (CYP3A protein, mouse); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.14.99.38 (cholesterol 25-hydroxylase)
[Em] Mês de entrada:1111
[Cu] Atualização por classe:160307
[Lr] Data última revisão:
160307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110518
[St] Status:MEDLINE
[do] DOI:10.1194/jlr.M014084



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