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[PMID]:24563544
[Au] Autor:Hamouda AK; Stewart DS; Chiara DC; Savechenkov PY; Bruzik KS; Cohen JB
[Ad] Endereço:Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (A.K.H., D.C.C., J.B.C.); Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (D.S.S.); and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois (P.Y.S., K.S.B.).
[Ti] Título:Identifying barbiturate binding sites in a nicotinic acetylcholine receptor with [3H]allyl m-trifluoromethyldiazirine mephobarbital, a photoreactive barbiturate.
[So] Source:Mol Pharmacol;85(5):735-46, 2014 May.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:At concentrations that produce anesthesia, many barbituric acid derivatives act as positive allosteric modulators of inhibitory GABAA receptors (GABAARs) and inhibitors of excitatory nicotinic acetylcholine receptors (nAChRs). Recent research on [(3)H]R-mTFD-MPAB ([(3)H]R-5-allyl-1-methyl-5-(m-trifluoromethyldiazirinylphenyl)barbituric acid), a photoreactive barbiturate that is a potent and stereoselective anesthetic and GABAAR potentiator, has identified a second class of intersubunit binding sites for general anesthetics in the α1ß3γ2 GABAAR transmembrane domain. We now characterize mTFD-MPAB interactions with the Torpedo (muscle-type) nAChR. For nAChRs expressed in Xenopus oocytes, S- and R-mTFD-MPAB inhibited ACh-induced currents with IC50 values of 5 and 10 µM, respectively. Racemic mTFD-MPAB enhanced the equilibrium binding of [(3)H]ACh to nAChR-rich membranes (EC50 = 9 µM) and inhibited binding of the ion channel blocker [(3)H]tenocyclidine in the nAChR desensitized and resting states with IC50 values of 2 and 170 µM, respectively. Photoaffinity labeling identified two binding sites for [(3)H]R-mTFD-MPAB in the nAChR transmembrane domain: 1) a site within the ion channel, identified by photolabeling in the nAChR desensitized state of amino acids within the M2 helices of each nAChR subunit; and 2) a site at the γ-α subunit interface, identified by photolabeling of γMet299 within the γM3 helix at similar efficiency in the resting and desensitized states. These results establish that mTFD-MPAB is a potent nAChR inhibitor that binds in the ion channel preferentially in the desensitized state and binds with lower affinity to a site at the γ-α subunit interface where etomidate analogs bind that act as positive and negative nAChR modulators.
[Mh] Termos MeSH primário: Barbitúricos/metabolismo
Mefobarbital/metabolismo
Marcadores de Fotoafinidade/metabolismo
Receptores Nicotínicos/metabolismo
Trítio/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Barbitúricos/química
Sítios de Ligação/fisiologia
Relação Dose-Resposta a Droga
Feminino
Mefobarbital/química
Dados de Sequência Molecular
Marcadores de Fotoafinidade/química
Receptores Nicotínicos/química
Torpedo
Trítio/química
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Barbiturates); 0 (Photoaffinity Labels); 0 (Receptors, Nicotinic); 10028-17-8 (Tritium); 5NC67NU76B (Mephobarbital); WQ92Y2793G (barbituric acid)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140225
[St] Status:MEDLINE
[do] DOI:10.1124/mol.113.090985


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[PMID]:23205958
[Au] Autor:Bialer M
[Ad] Endereço:School of Pharmacy, Institute for Drug Research, Faculty of Medicine, and David R. Bloom Center for Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. bialer@md.huji.ac.il
[Ti] Título:How did phenobarbital's chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?
[So] Source:Epilepsia;53 Suppl 8:3-11, 2012 Dec.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative-hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.
[Mh] Termos MeSH primário: Anticonvulsivantes/química
Descoberta de Drogas/história
Fenobarbital/química
[Mh] Termos MeSH secundário: Anticonvulsivantes/história
Carbamazepina/química
Carbamazepina/história
Descoberta de Drogas/métodos
Epilepsia/tratamento farmacológico
Epilepsia/história
Etossuximida/química
Etossuximida/história
História do Século XX
Seres Humanos
Mefenitoína/química
Mefenitoína/história
Mefobarbital/química
Mefobarbital/história
Fenobarbital/análogos & derivados
Fenobarbital/história
Fenitoína/análogos & derivados
Fenitoína/química
Fenitoína/história
Primidona/química
Primidona/história
Relação Estrutura-Atividade
Succinimidas/química
Succinimidas/história
Ácido Valproico/química
Ácido Valproico/história
[Pt] Tipo de publicação:HISTORICAL ARTICLE; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Succinimides); 0G76K8X6C0 (methsuximide); 13AFD7670Q (Primidone); 33CM23913M (Carbamazepine); 432SI047GA (eterobarb); 5NC67NU76B (Mephobarbital); 5SEH9X1D1D (Ethosuximide); 614OI1Z5WI (Valproic Acid); 6158TKW0C5 (Phenytoin); B4SF212641 (fosphenytoin); R420KW629U (Mephenytoin); YQE403BP4D (Phenobarbital)
[Em] Mês de entrada:1302
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121205
[St] Status:MEDLINE
[do] DOI:10.1111/epi.12024


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[PMID]:22734650
[Au] Autor:Savechenkov PY; Zhang X; Chiara DC; Stewart DS; Ge R; Zhou X; Raines DE; Cohen JB; Forman SA; Miller KW; Bruzik KS
[Ad] Endereço:Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA.
[Ti] Título:Allyl m-trifluoromethyldiazirine mephobarbital: an unusually potent enantioselective and photoreactive barbiturate general anesthetic.
[So] Source:J Med Chem;55(14):6554-65, 2012 Jul 26.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray crystallography. Additionally, we obtained the (3)H-labeled ligand with high specific radioactivity. R-(-)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC(50) approaches those for propofol and etomidate, whereas S-(+)-14 is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(-)-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human α1ß2/3γ2L GABA(A) receptors. Finally, R-(-)-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both α1 and ß3 subunits of human α1ß3 GABA(A) receptors. These results indicate R-(-)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors.
[Mh] Termos MeSH primário: Anestésicos Gerais/química
Anestésicos Gerais/farmacologia
Azirinas/química
Luz
Mefobarbital/química
Mefobarbital/farmacologia
[Mh] Termos MeSH secundário: Anestésicos Gerais/metabolismo
Seres Humanos
Mefobarbital/metabolismo
Receptores de GABA-A/metabolismo
Solubilidade
Estereoisomerismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Anesthetics, General); 0 (Azirines); 0 (Receptors, GABA-A); 5NC67NU76B (Mephobarbital)
[Em] Mês de entrada:1210
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120628
[St] Status:MEDLINE
[do] DOI:10.1021/jm300631e


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[PMID]:22342565
[Au] Autor:Mairinger S; Bankstahl JP; Kuntner C; Römermann K; Bankstahl M; Wanek T; Stanek J; Löscher W; Müller M; Erker T; Langer O
[Ad] Endereço:Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
[Ti] Título:The antiepileptic drug mephobarbital is not transported by P-glycoprotein or multidrug resistance protein 1 at the blood-brain barrier: a positron emission tomography study.
[So] Source:Epilepsy Res;100(1-2):93-103, 2012 Jun.
[Is] ISSN:1872-6844
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Aim of this study was to determine whether the carbon-11-labeled antiepileptic drug [(11)C]mephobarbital is a substrate of P-glycoprotein (Pgp) and can be used to assess Pgp function at the blood-brain barrier (BBB) with positron emission tomography (PET). We performed paired PET scans in rats, wild-type (FVB) and Mdr1a/b((-/-)) mice, before and after intravenous administration of the Pgp inhibitor tariquidar (15mg/kg). Brain-to-blood AUC(0-60) ratios in rats and brain AUC(0-60) values of [(11)C]mephobarbital in wild-type and Mdr1a/b((-/-)) mice were similar in scans 1 and 2, respectively, suggesting that in vivo brain distribution of [(11)C]mephobarbital is not influenced by Pgp efflux. Absence of Pgp transport was confirmed in vitro by performing concentration equilibrium transport assay in cell lines transfected with MDR1 or Mdr1a. PET experiments in wild-type mice, with and without pretreatment with the multidrug resistance protein (MRP) inhibitor MK571 (20mg/kg), and in Mrp1((-/-)) mice suggested that [(11)C]mephobarbital is also not transported by MRPs at the murine BBB, which was also supported by in vitro transport experiments using human MRP1-transfected cells. Our results are surprising, as phenobarbital, the N-desmethyl derivative of mephobarbital, has been shown to be a substrate of Pgp, which suggests that N-methylation abolishes Pgp affinity of barbiturates.
[Mh] Termos MeSH primário: Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo
Anticonvulsivantes/metabolismo
Barreira Hematoencefálica/diagnóstico por imagem
Barreira Hematoencefálica/metabolismo
Mefobarbital/metabolismo
Tomografia por Emissão de Pósitrons/métodos
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
Animais
Transporte Biológico/fisiologia
Feminino
Seres Humanos
Células LLC-PK1
Camundongos
Camundongos Knockout
Ligação Proteica/fisiologia
Ratos
Ratos Sprague-Dawley
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Anticonvulsants); 0 (multidrug resistance protein 3); 5NC67NU76B (Mephobarbital)
[Em] Mês de entrada:1302
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120221
[St] Status:MEDLINE
[do] DOI:10.1016/j.eplepsyres.2012.01.012


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[PMID]:19218807
[Au] Autor:Aksamija A; Habek D; Stanojevic M; Ujevic B
[Ad] Endereço:Clinic of Gynecology and Obstetrics, Sveti Duh General Hospital, Zagreb, Croatia.
[Ti] Título:Fetal malformations associated with the use of methylphenobarbital and carbamazepine during pregnancy. Two case reports and review of the literature.
[So] Source:Fetal Diagn Ther;25(1):79-82, 2009.
[Is] ISSN:1421-9964
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:The use of antiepileptic drugs (AEDs) during pregnancy has been associated with an increased risk of major and minor fetal malformations. This paper describes 2 infants with malformations born to epileptic mothers who used AEDs throughout pregnancy. In the first case, the AED used for seizure control was methylphenobarbital, while in the second case the patient had been prescribed carbamazepine. We noted major and minor congenital malformations in both infants exposed in utero to these anticonvulsant drugs. Pregnant women still experience poor obstetrical care because they report to tertiary centers at the end of their pregnancy or when in labor, making it difficult to provide proper medical care for both the infant and the mother.
[Mh] Termos MeSH primário: Anormalidades Induzidas por Medicamentos/etiologia
Anticonvulsivantes/efeitos adversos
Carbamazepina/efeitos adversos
Exposição Materna
Mefobarbital/efeitos adversos
[Mh] Termos MeSH secundário: Anormalidades Induzidas por Medicamentos/epidemiologia
Adulto
Anticonvulsivantes/uso terapêutico
Carbamazepina/uso terapêutico
Epilepsia/tratamento farmacológico
Feminino
Seres Humanos
Masculino
Mefobarbital/uso terapêutico
Gravidez
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anticonvulsants); 33CM23913M (Carbamazepine); 5NC67NU76B (Mephobarbital)
[Em] Mês de entrada:0911
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090217
[St] Status:MEDLINE
[do] DOI:10.1159/000201945


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[PMID]:19190392
[Au] Autor:Janik A; Olech A; Stasiewicz-Urban A; Stadnicka K
[Ad] Endereço:Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland. janik@chemia.uj.edu.pl
[Ti] Título:The influence of sulfur substituents on the molecular geometry and packing of thio derivatives of N-methylphenobarbital.
[So] Source:Acta Crystallogr C;65(Pt 2):o70-5, 2009 Feb.
[Is] ISSN:1600-5759
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The room-temperature crystal structures of four new thio derivatives of N-methylphenobarbital [systematic name: 5-ethyl-1-methyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione], C(13)H(14)N(2)O(3), are compared with the structure of the parent compound. The sulfur substituents in N-methyl-2-thiophenobarbital [5-ethyl-1-methyl-5-phenyl-2-thioxo-1,2-dihydropyrimidine-4,6(3H,5H)-dione], C(13)H(14)N(2)O(2)S, N-methyl-4-thiophenobarbital [5-ethyl-1-methyl-5-phenyl-4-thioxo-3,4-dihydropyrimidine-2,6(1H,5H)-dione], C(13)H(14)N(2)O(2)S, and N-methyl-2,4,6-trithiophenobarbital [5-ethyl-1-methyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trithione], C(13)H(14)N(2)S(3), preserve the heterocyclic ring puckering observed for N-methylphenobarbital (a half-chair conformation), whereas in N-methyl-2,4-dithiophenobarbital [5-ethyl-1-methyl-5-phenyl-2,4-dithioxo-1,2,3,4-tetrahydropyrimidine-6(5H)-one], C(13)H(14)N(2)OS(2), significant flattening of the ring was detected. The number and positions of the sulfur substituents influence the packing and hydrogen-bonding patterns of the derivatives. In the cases of the 2-thio, 4-thio and 2,4,6-trithio derivatives, there is a preference for the formation of a ring motif of the R(2)(2)(8) type, which is also a characteristic of N-methylphenobarbital, whereas a C(6) chain forms in the 2,4-dithio derivative. The preferences for hydrogen-bond formation, which follow the sequence of acceptor position 4 > 2 > 6, confirm the differences in the nucleophilic properties of the C atoms of the heterocyclic ring and are consistent with the course of N-methylphenobarbital thionation reactions.
[Mh] Termos MeSH primário: Mefobarbital/análogos & derivados
Enxofre/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Ligações de Hidrogênio
Mefobarbital/química
Modelos Moleculares
Conformação Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
5NC67NU76B (Mephobarbital); 70FD1KFU70 (Sulfur)
[Em] Mês de entrada:0904
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090205
[St] Status:MEDLINE
[do] DOI:10.1107/S0108270108043060


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[PMID]:17225740
[Au] Autor:Heeringa-Karreman M; van Munster ET
[Ad] Endereço:Jeroen Bosch Ziekenhuis, locatie Liduina, Postbus 10.100, 5280 GA Boxtel.
[Ti] Título:[Intoxication due to replacement of the precursor methylphenobarbital by phenobarbital].
[Ti] Título:Intoxicatie door het vervangen van de precursor methylfenobarbital door fenobarbital..
[So] Source:Ned Tijdschr Geneeskd;150(17):977-9, 2006 Apr 29.
[Is] ISSN:0028-2162
[Cp] País de publicação:Netherlands
[La] Idioma:dut
[Ab] Resumo:An 80-year-old woman with a history of familial primary generalised epilepsy presented to the outpatient clinic with complaints of dizziness, confusion, dullness and feeling of'being worthless'. It turned out that she had been using medication for some time in which the chemical nature of the pharmacologically active ingredient had been changed: methylphenobarbital 60 mg t.i.d. had been replaced by phenobarbital 60 mg t.i.d. The resultant phenobarbital concentration was much higher than the concentration to which she was accustomed. At the same dosage, phenobarbital is more active than methylphenobarbital. When one compound ofa pharmacologically active substance is replaced by a different compound, the dosage should be corrected for both the chemical structure, such as the molecular weight, and the pharmacokinetic properties such as absorption, metabolism and biological availability.
[Mh] Termos MeSH primário: Anticonvulsivantes/efeitos adversos
Anticonvulsivantes/metabolismo
Mefobarbital/metabolismo
Fenobarbital/efeitos adversos
Fenobarbital/metabolismo
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Disponibilidade Biológica
Feminino
Seres Humanos
Absorção Intestinal
Mefobarbital/administração & dosagem
Mefobarbital/efeitos adversos
[Pt] Tipo de publicação:CASE REPORTS; ENGLISH ABSTRACT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 5NC67NU76B (Mephobarbital); YQE403BP4D (Phenobarbital)
[Em] Mês de entrada:0702
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:070118
[St] Status:MEDLINE


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[PMID]:15499191
[Au] Autor:Morita J; Kobayashi K; Wanibuchi A; Kimura M; Irie S; Ishizaki T; Chiba K
[Ad] Endereço:Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
[Ti] Título:A novel single nucleotide polymorphism (SNP) of the CYP2C19 gene in a Japanese subject with lowered capacity of mephobarbital 4'-hydroxylation.
[So] Source:Drug Metab Pharmacokinet;19(3):236-8, 2004 Jun.
[Is] ISSN:1347-4367
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We sequenced all nine exons and exon-intron junctions of the cytochrome P450 2C19 (CYP2C19) gene from a Japanese subject with a lowered capacity of CYP2C19-mediated 4'-hydroxylation after an oral administration of mephobarbital. We found a novel single nucleotide polymorphism (SNP) of CYP2C19 gene as follows: SNP, 040110MoritaJ001; GENENAME: CYP2C19; ACCESSION NUMBER: NT_030059.8; LENGTH; 25 bases; 5'-GAGGGCCTGGCCC/TGCATGGAGCTGT-3'. The SNP (168946C>T) induced an amino acid alteration (Arg442Cys) located in exon 9 close to the heme-binding region of CYP2C19, which may result in the decrease in the catalytic properties of CYP2C19. A new allele having this SNP was designated as CYP2C19*16.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/deficiência
Hidrocarboneto de Aril Hidroxilases/genética
Grupo com Ancestrais do Continente Asiático/genética
Mefobarbital/metabolismo
Oxigenases de Função Mista/deficiência
Oxigenases de Função Mista/genética
Polimorfismo de Nucleotídeo Único/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos/genética
Arginina/genética
Cisteína/genética
Citocromo P-450 CYP2C19
Ativação Enzimática/genética
Triagem de Portadores Genéticos
Seres Humanos
Hidroxilação
Masculino
Dados de Sequência Molecular
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
5NC67NU76B (Mephobarbital); 94ZLA3W45F (Arginine); EC 1.- (Mixed Function Oxygenases); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); K848JZ4886 (Cysteine)
[Em] Mês de entrada:0411
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:041023
[St] Status:MEDLINE


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[PMID]:15284537
[Au] Autor:Kobayashi K; Morita J; Chiba K; Wanibuchi A; Kimura M; Irie S; Urae A; Ishizaki T
[Ad] Endereço:Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
[Ti] Título:Pharmacogenetic roles of CYP2C19 and CYP2B6 in the metabolism of R- and S-mephobarbital in humans.
[So] Source:Pharmacogenetics;14(8):549-56, 2004 Aug.
[Is] ISSN:0960-314X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES AND METHODS: We assessed the relationship between the metabolism of R- and S-mephobarbital (MPB) and genetic polymorphisms of cytochrome P450 (CYP) 2C19 and CYP2B6. Nine homozygous extensive metabolizers (homo-EMs, 2C19*1/2C19*1) of CYP2C19, ten heterozygous EMs (hetero-EMs, 2C19*1/2C19*2, 2C19*1/2C19*3) and eleven poor metabolizers (PMs, 2C19*2/2C19*2, 2C19*3/2C19*3, 2C19*2/2C19*3) recruited from a Japanese population, received an oral 200 mg-dose of racemic MPB. Blood and urine samples were collected, and R-MPB, S-MPB and the metabolites, phenobarbital (PB) and 4'-hydroxy-MPB, were measured. Each subject was also genotyped for CYP2B6 gene. RESULTS: The mean area under the plasma concentration-time curve (AUC) of R-MPB was 92-fold greater in PMs than in homo-EMs. R/S ratios for AUC of MPB were much higher in PMs than in EMs (homo- and hetero-). The cumulative urinary excretion of 4'-hydroxy-MPB up to 24 h postdose was 21-fold less in PMs than in homo-EMs. The metabolic ratio of AUCPB/(AUCS-MPB + AUCR-MPB) was higher in PMs than in EMs (homo- and hetero-). In addition, this metabolic ratio was lower in the carriers of CYP2B6*6 compared with that in its non-carriers. CONCLUSIONS: Our results indicate that the 4'-hydroxylation of R-MPB is mediated via CYP2C19 and that the rapid 4'-hydroxylation of R-MPB results in a marked difference in the pharmacokinetic profiles between R-MPB and S-MPB in the different CYP2C19 genotypic individuals. In addition, a minor fraction of the interindividual variability in PB formation from MPB may be explainable by the CYP2B6*6 allele.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/genética
Mefobarbital/farmacocinética
Oxigenases de Função Mista/genética
Oxirredutases N-Desmetilantes/genética
Polimorfismo Genético/genética
[Mh] Termos MeSH secundário: Adulto
Área Sob a Curva
Citocromo P-450 CYP2B6
Citocromo P-450 CYP2C19
Genótipo
Heterozigoto
Homozigoto
Seres Humanos
Hidroxilação
Japão
Masculino
Estrutura Molecular
Farmacogenética
Fenobarbital/sangue
Fenobarbital/urina
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
5NC67NU76B (Mephobarbital); EC 1.- (Mixed Function Oxygenases); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.5.- (Oxidoreductases, N-Demethylating); YQE403BP4D (Phenobarbital)
[Em] Mês de entrada:0502
[Cu] Atualização por classe:161124
[Lr] Data última revisão:
161124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:040731
[St] Status:MEDLINE


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[PMID]:13680065
[Au] Autor:Lubda D; Cabrera K; Nakanishi K; Lindner W
[Ad] Endereço:Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany. dieter.lubda@merck.de
[Ti] Título:Monolithic silica columns with chemically bonded beta-cyclodextrin as a stationary phase for enantiomer separations of chiral pharmaceuticals.
[So] Source:Anal Bioanal Chem;377(5):892-901, 2003 Nov.
[Is] ISSN:1618-2642
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:An enantioselective silica rod type chiral stationary phase (CSP) is presented; a novel combination of the well known enantiomer separation properties of beta-cyclodextrin and the unique properties concerning the flow behavior of silica monoliths. Two different synthesis routes are described, and it was found that the in situ modification of a plain silica rod column turned out to be the best. The chromatographic behaviour of the beta-cyclodextrin silica rod was studied and compared with a very similar commercially available beta-cyclodextrin bonded particulate material (ChiraDex). Even if the amount of beta-cyclodextrin bound to the silica rod was only about half of the amount of beta-cyclodextrin bound to ChiraDex) particles, good resolutions were achieved for a set of chiral test components like Chromakalin, Prominal, Oxazepam, Methadone and some other drugs. By taking advantage of the unique features of the silica rods relating to their flat H/u (Van Deemter) curves, fast enantiomer separations could be demonstrated.
[Mh] Termos MeSH primário: Cromatografia/métodos
Ciclodextrinas/química
Preparações Farmacêuticas/isolamento & purificação
Dióxido de Silício/química
[Mh] Termos MeSH secundário: Cromatografia/instrumentação
Compostos Heterocíclicos/química
Compostos Heterocíclicos/isolamento & purificação
Mefobarbital/química
Mefobarbital/isolamento & purificação
Metadona/química
Metadona/isolamento & purificação
Microscopia Eletrônica de Varredura
Norgestrel/química
Norgestrel/isolamento & purificação
Compostos Orgânicos/química
Compostos Orgânicos/isolamento & purificação
Oxazepam/química
Oxazepam/isolamento & purificação
Preparações Farmacêuticas/química
Estereoisomerismo
Temperatura Ambiente
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclodextrins); 0 (Heterocyclic Compounds); 0 (Organic Chemicals); 0 (Pharmaceutical Preparations); 3J8Q1747Z2 (Norgestrel); 5NC67NU76B (Mephobarbital); 6GOW6DWN2A (Oxazepam); 7631-86-9 (Silicon Dioxide); UC6VBE7V1Z (Methadone)
[Em] Mês de entrada:0402
[Cu] Atualização por classe:160512
[Lr] Data última revisão:
160512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:030919
[St] Status:MEDLINE



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