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[PMID]: 29203276 [Au] Autor: Lazarska KE; Dekker SJ; Vermeulen NPE; Commandeur JNM [Ad] Endereço: AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. [Ti] Título: Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism. [So] Source: Toxicol Lett;284:70-78, 2018 Mar 01. [Is] ISSN: 1879-3169 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury. Since no associations have been found with HLA-alleles, polymorphisms of genes encoding for proteins involved in the disposition of diclofenac may be important. Previous association studies showed that possession of the UGT2B7*2 and CYP2C8*4 alleles is more common in cases of diclofenac-induced DILI. In the present study, the metabolism of diclofenac by UGT2B7*2 and CYP2C8*4 was compared with their corresponding wild-type enzymes. Enzyme kinetic analysis revealed that recombinant UGT2B7*2 showed an almost 6-fold lower intrinsic clearance of diclofenac glucuronidation compared to UGT2B7*1. The mutant CYP2C8*4 showed approximately 35% reduced activity in the 4'-hydroxylation of diclofenac acyl glucuronide. Therefore, a decreased hepatic exposure to diclofenac acyl glucuronide is expected in patients with the UGT2B7*2 genotype. The increased risk for hepatotoxicity, therefore, might be the result from a shift to oxidative bioactivation to cytotoxic quinoneimines. [Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/metabolismo Citocromo P-450 CYP2C8/genética Diclofenaco/metabolismo Glucuronosiltransferase/genética Polimorfismo Genético [Mh] Termos MeSH secundário: Animais Doença Hepática Induzida por Substâncias e Drogas/metabolismo Escherichia coli/genética Glucuronídeos/metabolismo Hidroxilação Cinética Mutação Oxirredução Proteínas Recombinantes Células Sf9 [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Glucuronides); 0 (Recombinant Proteins); 144O8QL0L1 (Diclofenac); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); EC 2.4.1.- (UGT2B7 protein, human); EC 2.4.1.17 (Glucuronosyltransferase) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180221 [Lr] Data última revisão: 180221 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171206 [St] Status: MEDLINE

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[PMID]: 28451807 [Au] Autor: Matsuo M; Ito H; Takemura Y; Hattori M; Kawakami M; Takahashi N; Yamazaki M [Ad] Endereço: Department of Anesthesiology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. matsuo@itoigawa-hp.jp. [Ti] Título: Increased risk of paclitaxel-induced peripheral neuropathy in patients using clopidogrel: a retrospective pilot study. [So] Source: J Anesth;31(4):631-635, 2017 Aug. [Is] ISSN: 1438-8359 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: Paclitaxel-induced peripheral neuropathy (PIPN) is one of the serious adverse events associated with paclitaxel-based cancer treatments. A recent case study showed that the antiplatelet agent clopidogrel inhibits paclitaxel metabolism via cytochrome P450 (CYP) 2C8, resulting in severe PIPN. The aim of this study was to determine the impact of clopidogrel as a risk factor for the development of PIPN, using a retrospective cohort study. Data from paclitaxel-treated patients with or without clopidogrel and low-dose aspirin treatment were retrieved from medical charts. A total of 161 adult patients were included in this study: 135 were controls, 9 were clopidogrel-treated and 17 were aspirin-treated. The clopidogrel group had a greater proportion of males and a higher rate of comorbidities, such as diabetes mellitus and dyslipidemia, than the control group. However, patient characteristics were similar between the clopidogrel and aspirin groups. Severe PIPN was diagnosed in 3 (2.2%) and 2 (22.2%) patients in the control and clopidogrel groups, respectively (odds ratio: 12.0; p = 0.031). No patients in the aspirin group presented with severe neuropathy. These pilot data suggest that concomitant treatment with clopidogrel leads to a greater risk of PIPN. The avoidance of concomitant clopidogrel use may be effective in reducing clopidogrel-associated PIPN. [Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/efeitos adversos Paclitaxel/efeitos adversos Doenças do Sistema Nervoso Periférico/induzido quimicamente Ticlopidina/análogos & derivados [Mh] Termos MeSH secundário: Idoso Antineoplásicos Fitogênicos/administração & dosagem Estudos de Coortes Citocromo P-450 CYP2C8/metabolismo Feminino Seres Humanos Masculino Meia-Idade Razão de Chances Paclitaxel/administração & dosagem Projetos Piloto Inibidores da Agregação de Plaquetas/administração & dosagem Inibidores da Agregação de Plaquetas/efeitos adversos Estudos Retrospectivos Fatores de Risco Ticlopidina/administração & dosagem Ticlopidina/efeitos adversos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents, Phytogenic); 0 (Platelet Aggregation Inhibitors); A74586SNO7 (clopidogrel); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); OM90ZUW7M1 (Ticlopidine); P88XT4IS4D (Paclitaxel) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171207 [Lr] Data última revisão: 171207 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170429 [St] Status: MEDLINE [do] DOI: 10.1007/s00540-017-2362-y

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[PMID]: 28687336 [Au] Autor: Polonikov A; Kharchenko A; Bykanova M; Sirotina S; Ponomarenko I; Bocharova A; Vagaytseva K; Stepanov V; Bushueva O; Churnosov M; Solodilova M [Ad] Endereço: Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk 305041, Russian Federation; Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., K [Ti] Título: Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population. [So] Source: Gene;627:451-459, 2017 Sep 05. [Is] ISSN: 1879-0038 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Epoxyeicosatrienoic acids (EETs) are important vasoactive products of arachidonic acid metabolism with a wide range of biological actions in the cardiovascular system. The present study investigated whether single nucleotide polymorphisms (SNP) of genes coding cytochrome P450 2C subfamily, enzymes involved in biosynthesis of EETs, are associated with the risk of coronary heart disease (CHD). A total of 1255 unrelated Russian subjects comprising 561 patients with angiographically diagnosed CHD and 694 age- and sex-matched healthy subjects were included in the study. DNA samples from all study participants were genotyped for six common SNPs rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. SNP rs4918758 of CYP2C9 was associated with decreased risk of CHD (codominant model) at a borderline significance with odds ratio adjusted for sex and age 0.61 (95% CI: 0.41-0.92, P=0.038, Q=0.20). SNP rs9332242 of CYP2C9 showed a trend towards association with increased CHD risk in cigarette smokers (P=0.049, Q=0.29). Log-likelihood ratio test (LRT) pointed out epistatic interactions between rs9332242 and rs61886769 of CYP2C9 (codominant model, P =0.02), however, this P-value did not survive after correction for multiple tests. Bioinformatic analysis revealed a regulatory potential for a majority of the investigated SNPs. Our preliminary results demonstrate that polymorphisms of genes encoding CYP2C subfamily represent potential genetic markers of CHD susceptibility. Further studies are required to substantiate the contribution of these genes to the disease risk. [Mh] Termos MeSH primário: Doença das Coronárias/genética Citocromo P-450 CYP2C19/genética Citocromo P-450 CYP2C8/genética Citocromo P-450 CYP2C9/genética Polimorfismo de Nucleotídeo Único [Mh] Termos MeSH secundário: Idoso Estudos de Casos e Controles Feminino Seres Humanos Masculino Meia-Idade Federação Russa [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.14.14.1 (Cytochrome P-450 CYP2C8) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170920 [Lr] Data última revisão: 170920 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170709 [St] Status: MEDLINE

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[PMID]: 28447211 [Au] Autor: Tanabe Y; Shimizu C; Hamada A; Hashimoto K; Ikeda K; Nishizawa D; Hasegawa J; Shimomura A; Ozaki Y; Tamura N; Yamamoto H; Yunokawa M; Yonemori K; Takano T; Kawabata H; Tamura K; Fujiwara Y [Ad] Endereço: Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. [Ti] Título: Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese. [So] Source: Cancer Chemother Pharmacol;79(6):1179-1186, 2017 Jun. [Is] ISSN: 1432-0843 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: PURPOSE: Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer. METHODS: Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN. RESULTS: Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991-4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively). CONCLUSIONS: ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors. [Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/efeitos adversos Paclitaxel/efeitos adversos Doenças do Sistema Nervoso Periférico/induzido quimicamente Doenças do Sistema Nervoso Periférico/epidemiologia [Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética Adulto Idoso Envelhecimento/genética Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos Neoplasias da Mama/complicações Neoplasias da Mama/tratamento farmacológico Citocromo P-450 CYP2C8/genética Feminino Genótipo Seres Humanos Incidência Meia-Idade Transportadores de Ânions Orgânicos Sódio-Independentes/genética Farmacogenética Polimorfismo de Nucleotídeo Único Valor Preditivo dos Testes Estudos Prospectivos Células Receptoras Sensoriais Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto [Pt] Tipo de publicação: JOURNAL ARTICLE; OBSERVATIONAL STUDY [Nm] Nome de substância: 0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Antineoplastic Agents, Phytogenic); 0 (Organic Anion Transporters, Sodium-Independent); 0 (SLCO1B3 protein, human); 0 (Solute Carrier Organic Anion Transporter Family Member 1B3); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); P88XT4IS4D (Paclitaxel) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1007/s00280-017-3314-9

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[PMID]: 28444890 [Au] Autor: Arya V; Zhao P; Reynolds KS; Mishra P; Younis IR [Ad] Endereço: Division of Clinical Pharmacology IV, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA. [Ti] Título: Utilizing PBPK Modeling to Evaluate the Potential of a Significant Drug-Drug Interaction Between Clopidogrel and Dasabuvir: A Scientific Perspective. [So] Source: Clin Pharmacol Ther;102(4):578-580, 2017 Oct. [Is] ISSN: 1532-6535 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-ß-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK. [Mh] Termos MeSH primário: Citocromo P-450 CYP2C8/metabolismo Modelos Biológicos Sulfonamidas/farmacocinética Ticlopidina/análogos & derivados Uracila/análogos & derivados [Mh] Termos MeSH secundário: Antivirais/farmacocinética Citocromo P-450 CYP2C8/efeitos dos fármacos Combinação de Medicamentos Interações Medicamentosas Glucuronídeos Seres Humanos Compostos Macrocíclicos/administração & dosagem Compostos Macrocíclicos/farmacocinética Ritonavir/administração & dosagem Ritonavir/farmacocinética Sulfonamidas/administração & dosagem Ticlopidina/metabolismo Ticlopidina/farmacologia Uracila/administração & dosagem Uracila/farmacocinética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ABT-333); 0 (Antiviral Agents); 0 (Drug Combinations); 0 (Glucuronides); 0 (Macrocyclic Compounds); 0 (Sulfonamides); 0 (Viekira Pak); 56HH86ZVCT (Uracil); A74586SNO7 (clopidogrel); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); O3J8G9O825 (Ritonavir); OM90ZUW7M1 (Ticlopidine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170427 [St] Status: MEDLINE [do] DOI: 10.1002/cpt.699

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[PMID]: 28411400 [Au] Autor: Shebley M; Fu W; Badri P; Bow D; Fischer V [Ad] Endereço: Drug Metabolism, Pharmacokinetics and Bioanalysis, AbbVie Inc., North Chicago, Illinois, USA. [Ti] Título: Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir. [So] Source: Clin Pharmacol Ther;102(4):679-687, 2017 Oct. [Is] ISSN: 1532-6535 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-ß-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl-ß-D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5-1.9-fold for C and 1.9-2.8-fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant. [Mh] Termos MeSH primário: Citocromo P-450 CYP2C8/metabolismo Modelos Biológicos Sulfonamidas/farmacocinética Ticlopidina/análogos & derivados Uracila/análogos & derivados [Mh] Termos MeSH secundário: Antivirais/farmacocinética Área Sob a Curva Citocromo P-450 CYP2C8/efeitos dos fármacos Interações Medicamentosas Glucuronídeos Seres Humanos Técnicas In Vitro Ticlopidina/farmacocinética Ticlopidina/farmacologia Uracila/farmacocinética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ABT-333); 0 (Antiviral Agents); 0 (Glucuronides); 0 (Sulfonamides); 56HH86ZVCT (Uracil); A74586SNO7 (clopidogrel); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); OM90ZUW7M1 (Ticlopidine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170416 [St] Status: MEDLINE [do] DOI: 10.1002/cpt.689

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[PMID]: 28228413 [Au] Autor: Song G; Sun X; Hines RN; McCarver DG; Lake BG; Osimitz TG; Creek MR; Clewell HJ; Yoon M [Ad] Endereço: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of [Ti] Título: Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages. [So] Source: Drug Metab Dispos;45(5):468-475, 2017 May. [Is] ISSN: 1521-009X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth. The median CYP2C8 expression was significantly greater among samples from subjects older than 35 postnatal days ( 122) compared with fetal samples and those from very young infants (fetal to 35 days postnatal, 100) (0.00 vs. 13.38 pmol/mg microsomal protein; < 0.0001). In contrast, the median CYP1A2 expression was significantly greater after 15 months postnatal age ( 55) than in fetal and younger postnatal samples (fetal to 15 months postnatal, 167) (0.0167 vs. 2.354 pmol/mg microsomal protein; < 0.0001). CYP2C8, but not CYP1A2, protein levels significantly correlated with those of CYP2C9, CYP2C19, and CYP3A4 ( < 0.001), consistent with CYP2C8 and CYP1A2 ontogeny probably being controlled by different mechanisms. This study provides key data for the physiologically based pharmacokinetic model-based prediction of age-dependent pyrethroid metabolism, which will be used for IVIVE to support pyrethroid risk assessment for early life stages. [Mh] Termos MeSH primário: Envelhecimento/metabolismo Citocromo P-450 CYP1A2/genética Citocromo P-450 CYP2C8/genética Expressão Gênica Fígado/metabolismo Microssomos Hepáticos/metabolismo [Mh] Termos MeSH secundário: Adolescente Adulto Envelhecimento/genética Criança Pré-Escolar Feminino Desenvolvimento Fetal/genética Ontologia Genética Idade Gestacional Seres Humanos Técnicas In Vitro Lactente Recém-Nascido Fígado/embriologia Fígado/enzimologia Masculino Microssomos Hepáticos/enzimologia Medição de Risco Xenobióticos/metabolismo Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Xenobiotics); EC 1.14.14.1 (CYP1A2 protein, human); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1A2); EC 1.14.14.1 (Cytochrome P-450 CYP2C8) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170825 [Lr] Data última revisão: 170825 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170224 [St] Status: MEDLINE [do] DOI: 10.1124/dmd.116.074583

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[PMID]: 28224612 [Au] Autor: Agergaard K; Mau-Sørensen M; Stage TB; Jørgensen TL; Hassel RE; Steffensen KD; Pedersen JW; Milo M; Poulsen SH; Pottegård A; Hallas J; Brøsen K; Bergmann TK [Ad] Endereço: Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark. [Ti] Título: Clopidogrel-Paclitaxel Drug-Drug Interaction: A Pharmacoepidemiologic Study. [So] Source: Clin Pharmacol Ther;102(3):547-553, 2017 Sep. [Is] ISSN: 1532-6535 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-ß-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age- and sex-matched controls treated with paclitaxel and low-dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9-3.0). Among those receiving a high-dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high-dose paclitaxel. [Mh] Termos MeSH primário: Citocromo P-450 CYP2C8/metabolismo Paclitaxel/administração & dosagem Doenças do Sistema Nervoso Periférico/induzido quimicamente Inibidores da Agregação de Plaquetas/administração & dosagem Ticlopidina/análogos & derivados [Mh] Termos MeSH secundário: Idoso Aspirina/administração & dosagem Relação Dose-Resposta a Droga Interações Medicamentosas Feminino Seres Humanos Fígado/metabolismo Masculino Meia-Idade Paclitaxel/efeitos adversos Paclitaxel/farmacocinética Doenças do Sistema Nervoso Periférico/epidemiologia Farmacoepidemiologia Inibidores da Agregação de Plaquetas/efeitos adversos Inibidores da Agregação de Plaquetas/farmacocinética Estudos Retrospectivos Índice de Gravidade de Doença Ticlopidina/administração & dosagem Ticlopidina/efeitos adversos Ticlopidina/farmacocinética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Platelet Aggregation Inhibitors); A74586SNO7 (clopidogrel); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); OM90ZUW7M1 (Ticlopidine); P88XT4IS4D (Paclitaxel); R16CO5Y76E (Aspirin) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170822 [Lr] Data última revisão: 170822 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170223 [St] Status: MEDLINE [do] DOI: 10.1002/cpt.674

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[PMID]: 28099407 [Au] Autor: Yin SJ; Qi HM; Wang X; Zhang P; Lu Y; Wei MJ; Li P; Qi GZ; Lou YQ; Lu C; Zhang GL [Ad] Endereço: aDepartment of Pharmacology,School of Basic Medical Sciences, Peking University bDepartment of Pharmacokinetics, Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China cDepartment of Drug Metabolism & Pharmacokinetics, Biogen, Cambridge, Massachusetts, USA. [Ti] Título: Effects of functional CYP2C8,CYP2C9,CYP3A5,and ABCB1 genetic variants on the pharmacokinetics of insulin sensitizer pioglitazone in Chinese Han individuals. [So] Source: Pharmacogenet Genomics;27(4):125-134, 2017 Apr. [Is] ISSN: 1744-6880 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND AND OBJECTIVES: Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals. PARTICIPANTS AND METHODS: Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals. After a single oral dose of 30 mg pioglitazone, the plasma concentrations of the parent drug and of two major active metabolites M-III and M-IV were measured using a validated LC-MS/MS in 21 (genotyping CYP3A5 and ABCB1) of these 244 volunteers. RESULTS: The results confirmed that the unique frequencies of CYP2C8*2 (0.0%), CYP2C8*3 (0.0%), and CYP2C9*2 (0.0%) alleles were significantly different from those reported in Whites and Africans, and there were only 10 variant CYP2C9*1/*3 heterozygous (CYP2C9*3 carriers) among 244 Chinese individuals. These results were similar to those reported in Asian ethnic populations, including the Chinese. Unexpectedly, the pioglitazone AUC0-48 in CYP2C9*3 carriers was lower (50.8%), whereas the AUC0-48 ratios of metabolites M-III/pioglitazone and M-IV/pioglitazone increased to 134.3 and 155.8%, respectively, compared with the wild-type CYP2C9*1/*1 homozygous. Moreover, this phenomenon was not observed in individuals with genetic variants of CYP3A5*3 and ABCB1 (C1236T). CONCLUSION: The present research suggests that the CYP2C8, CYP3A5, and ABCB1 genes play no significant role in the interindividual variation of pioglitazone pharmacokinetics, whereas CYP2C9*3 carriers are likely to accelerate the metabolism of this antidiabetic drug in the Chinese Han ethnic population. [Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética Redes Reguladoras de Genes Hipoglicemiantes/administração & dosagem Polimorfismo de Nucleotídeo Único Tiazolidinedionas/administração & dosagem [Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética Administração Oral Adulto Grupo com Ancestrais do Continente Asiático/etnologia China/etnologia Citocromo P-450 CYP2C8/genética Citocromo P-450 CYP2C9/genética Citocromo P-450 CYP3A/genética Feminino Genótipo Seres Humanos Hipoglicemiantes/farmacocinética Masculino Variantes Farmacogenômicos Tiazolidinedionas/farmacocinética Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Hypoglycemic Agents); 0 (Thiazolidinediones); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (CYP3A5 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); EC 1.14.14.1 (Cytochrome P-450 CYP3A); X4OV71U42S (pioglitazone) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170119 [St] Status: MEDLINE [do] DOI: 10.1097/FPC.0000000000000265

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[PMID]: 27867185 [Au] Autor: Jang Y; Chung HJ; Hong JW; Yun CW; Chung H [Ad] Endereço: Center for Neuro-Medicine, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea. [Ti] Título: Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase. [So] Source: Acta Pharmacol Sin;38(1):133-145, 2017 Jan. [Is] ISSN: 1745-7254 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo. [Mh] Termos MeSH primário: Composição de Medicamentos Absorção Intestinal Lipídeos/farmacocinética Óleos/farmacocinética Paclitaxel/farmacocinética [Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese Administração Oral Animais Bile/metabolismo Disponibilidade Biológica Caprilatos/química Citocromo P-450 CYP2C8/biossíntese Citocromo P-450 CYP3A/biossíntese Esquema de Medicação Ingestão de Alimentos Feminino Glicerídeos/química Glicerídeos/farmacocinética Intestino Delgado/metabolismo Lipídeos/química Fígado/metabolismo Camundongos Óleos/química Paclitaxel/administração & dosagem Paclitaxel/sangue Paclitaxel/química Polissorbatos/química Ratos Triglicerídeos/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Caprylates); 0 (Glycerides); 0 (Lipids); 0 (Oils); 0 (Polysorbates); 0 (Triglycerides); 6P92858988 (tricaprylin); C4YAD5F5G6 (monoolein); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); EC 1.14.14.1 (Cytochrome P-450 CYP3A); P88XT4IS4D (Paclitaxel) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161122 [St] Status: MEDLINE [do] DOI: 10.1038/aps.2016.105

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