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1.
Biomed Chromatogr ; 33(2): e4388, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30238481

RESUMO

In this study, we developed a method for the determination of Penicillium griseofulvum-oriented pyripyropene A (PPPA), a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse and human plasma and validated it using liquid chromatography-tandem mass spectrometry. Pyripyropene A (PPPA) and an internal standard, carbamazepine, were separated using a Xterra MS C18 column with a mixture of acetonitrile and 0.1% formic acid as the mobile phase. The ion transitions monitored in positive-ion mode [M + H]+ of multiple-reaction monitoring (MRM) were m/z 148.0 from m/z 584.0 for PPPA and m/z 194.0 from m/z 237.0 for the internal standard. The detector response was specific and linear for PPPA at concentrations within the range from 1 to 5,000 ng/mL. The intra-/inter-day precision and accuracy of the method was acceptable by the criteria for assay validation. The matrix effects of PPPA ranged from 97.6 to 104.2% and from 93.3 to 105.3% in post-preparative mouse and human plasma samples, respectively. PPPA was also stable under various processing and/or handling conditions. Finally, PPPA concentrations in the mouse plasma samples could be measured after intravenous, intraperitoneal, or oral administration of PPPA, suggesting that the assay is useful for pharmacokinetic studies on mice and applicable to human studies.


Assuntos
Cromatografia Líquida/métodos , Penicillium/química , Piridinas/sangue , Piridinas/farmacocinética , Sesquiterpenos/sangue , Sesquiterpenos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Piridinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/química , Esterol O-Aciltransferase/antagonistas & inibidores
2.
Xenobiotica ; 49(7): 823-832, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29972081

RESUMO

The purpose of this study was to evaluate the acute effect of a small molecule inhibitor of DGAT-1 on triglycerides (TG) and cholesterol in polygenic type 2 diabetic TallyHo/JngJ (TH) mice. PF-04620110, a potent and selective DGAT-1 inhibitor, was used as a model compound in this study and which was administered to TH and ICR mice. The concentration of the model compound that produced 50% of maximum lowering of TG level (IC50) in TH mice was not significantly different from that in ICR mice, when estimated using the model-based pharmacokinetic and pharmacodynamic assay, a two-compartmental model and an indirect response model. The clearance of the inhibitor in TH mice was fivefold higher than that in ICR mice, suggesting significantly altered pharmacokinetics. Moreover, the in vitro metabolic elimination kinetic parameters (ke,met), determined using liver microsomes from TH and ICR mice were 1.24 ± 0.14 and 0.174 ± 0.116 min-1, respectively. Thus, we report that the differences in the acute effects of the small molecule DAGT-1 inhibitor between TH mice and ICR mice can be attributed to altered pharmacokinetics caused by an altered metabolic rate for the compound in TH mice.


Assuntos
Colesterol/sangue , Diabetes Mellitus Tipo 2 , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Modelos Biológicos , Oxazepinas , Triglicerídeos/sangue , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diacilglicerol O-Aciltransferase/genética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Oxazepinas/farmacocinética , Oxazepinas/farmacologia
3.
Eur J Pharm Sci ; 96: 28-36, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27619346

RESUMO

The objective of this study was to examine the feasibility of functional expression of the human organic anion transporting polypeptide 1B1 (hOATP1B1) forms in the liver of the mouse. After the mouse received the gene of interest (i.e., luciferase as the reporter or hOATP1B1) via hydrodynamic gene delivery (HGD) method, the expression was found to be liver-specific while alterations in the serum biochemistry and hepatocyte histology were apparently transient and reversible. The reporter activity was also detected in the plasma, but not in the blood cell in mice that received HGD, suggesting that the protein is probably released due to transiently increased permeability in hepatocytes by HGD. Using this delivery condition, the expression of hOATP1B1 was readily detected in the liver, but not in other tissues, of the mice receiving HGD for the transporter gene. Compared with the sham control mice, the uptake of pravastatin into the liver increased significantly in mice receiving hOATP1B1 wild type; the uptake parameters decreased consistently in mice expressing the 521T>C variant compared with that of the wild type control. These observations suggest that the functional expression of human transporter gene in mice is feasible, further suggesting that this treatment is practically useful in the pharmacokinetic studies for hOATP1B1 substrates.


Assuntos
Técnicas de Transferência de Genes , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Animais , Genes Reporter , Variação Genética , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Luciferases/genética , Masculino , Camundongos Endogâmicos ICR , Pravastatina/sangue , Pravastatina/farmacocinética
4.
Planta Med ; 82(1-2): 121-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26366751

RESUMO

To examine whether quercetin interacts with vitamin D receptor, we investigated the effects of quercetin on vitamin D receptor activity in human intestinal Caco-2 cells. The effects of quercetin on the expression of the vitamin D receptor target genes, vitamin D3 24-hydroxylase, cytochrome P450 3A4, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were measured using quantitative polymerase chain reaction. The vitamin D receptor siRNA was used to assess the involvement of the vitamin D receptor. Vitamin D receptor activation using a vitamin D responsive element-mediated cytochrome P450 3A4 reporter gene assay was investigated in Caco-2 cells transfected with human vitamin D receptor. We also studied the magnitude of the vitamin D receptor activation and/or synergism between 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and quercetin-like flavonoids. Slight but significant increases in the mRNA expression of cytochrome P450 3A4, vitamin D3 24-hydroxylase, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were observed after 3 days of continual quercetin treatment. The silencing effect of vitamin D receptor by vitamin D receptor siRNA in Caco-2 cells significantly attenuated the induction of the vitamin D receptor target genes. Moreover, quercetin significantly enhanced cytochrome P450 3A4 reporter activity in Caco-2 cells in a dose-dependent manner, and the expression of exogenous vitamin D receptor further stimulated the vitamin D receptor activity. Quercetin-like flavonoids such as kaempferol stimulated the vitamin D receptor activity in a manner similar to that seen with quercetin. Taken together, the data indicates that quercetin upregulates cytochrome P450 3A4 and multidrug resistance protein 1 expression in Caco-2 cells likely via a vitamin D receptor-dependent pathway.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Citocromo P-450 CYP3A/metabolismo , Quercetina/farmacologia , Receptores de Calcitriol/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Células CACO-2 , Citocromo P-450 CYP3A/genética , Humanos , Estrutura Molecular , Quercetina/química , Transfecção , Regulação para Cima
5.
Biopharm Drug Dispos ; 36(6): 410-415, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25899769

RESUMO

The pharmacokinetics of lobeglitazone (LB) was studied after intravenous administration at a dose of 1 mg/kg and oral administration at doses of 0.1, 1 and 10 mg/kg in male and female rats. The area under the plasma concentration-time curve from time zero to infinity (AUCinf ) after intravenous administration was approximately 7.1 times higher in female rats than in male rats. In addition, the AUCinf in the case of oral administration was at least 4.4 times higher in female rats and appeared to increase in proportion to the dose in both genders. The in vitro half-lives were 18.8 ± 4.45 min and 60.7 ± 11.2 min, as evidenced by incubating liver microsomes obtained from male and female rats, respectively. As a result, the estimated CLint for LB for male rat liver microsomes (0.0779 ± 0.0233 ml/min/mg protein) was much higher than that for female rat liver microsomes (0.0233 ± 0.0039 ml/min/mg protein, p < 0.05). These observations suggest that there are gender differences in the pharmacokinetics and hepatic metabolism for LB in rats. Copyright © 2015 John Wiley & Sons, Ltd.

6.
J Neurosci ; 34(38): 12725-37, 2014 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-25232110

RESUMO

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Mitochondrial complex I impairment in PD is modeled in vitro by the susceptibility of dopaminergic neurons to the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+). In the present study, we demonstrate that microRNA-7 (miR-7), which is expressed in tyrosine hydroxylase-positive nigral neurons in mice and humans, protects cells from MPP+-induced toxicity in dopaminergic SH-SY5Y cells, differentiated human neural progenitor ReNcell VM cells, and primary mouse neurons. RelA, a component of nuclear factor-κB (NF-κB), was identified to be downregulated by miR-7 using quantitative proteomic analysis. Through a series of validation experiments, it was confirmed that RelA mRNA is a target of miR-7 and is required for cell death following MPP+ exposure. Further, RelA mediates MPP+-induced suppression of NF-κB activity, which is essential for MPP+-induced cell death. Accordingly, the protective effect of miR-7 is exerted through relieving NF-κB suppression by reducing RelA expression. These findings provide a novel mechanism by which NF-κB suppression, rather than activation, underlies the cell death mechanism following MPP+ toxicity, have implications for the pathogenesis of PD, and suggest miR-7 as a therapeutic target for this disease.


Assuntos
1-Metil-4-fenilpiridínio/antagonistas & inibidores , MicroRNAs/fisiologia , Fármacos Neuroprotetores/metabolismo , Doença de Parkinson Secundária/prevenção & controle , Fator de Transcrição RelA/biossíntese , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Regulação para Baixo , Humanos , Camundongos , MicroRNAs/biossíntese , MicroRNAs/genética , NF-kappa B/biossíntese , Neurônios/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Substância Negra/metabolismo , Fator de Transcrição RelA/genética , Transfecção , alfa-Sinucleína/genética
7.
Biomed Chromatogr ; 27(7): 846-52, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23420715

RESUMO

In this study, we developed a method for the determination of PF-04620110 (2-{(1r,4r)-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl}acetic acid), a novel diacylglycerol acyltransferase 1 (DGAT-1) inhibitor, in rat plasma and validated it using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rat plasma samples were processed following a protein precipitation method by using acetonitrile and were then injected into an LC-MS/MS system for quantification. PF-04620110 and imipramine (internal standard) were separated using a Hypersil Gold C18 column, with a mixture of acetonitrile and 10 mm ammonium formate (90:10, v/v) as the mobile phase. The ion transitions monitored in positive-ion mode [M + H](+) of multiple-reaction monitoring were m/z 397.0 → 260.2 for PF-04620110 and m/z 280.8 → 86.0 for imipramine. The detector response was specific and linear for PF-04620110 at concentrations within the range 0.05-50 µg/mL and the signal-to-noise ratios for the samples were ≥10. The intra- and inter-day precision and accuracy of the method matched the acceptance criteria for assay validation. PF-04620110 was stable under various processing and/or handling conditions. PF-04620110 concentrations in the rat plasma samples could be measured up to 24 h after intravenous or oral administration of PF-04620110, suggesting that the assay is useful for pharmacokinetic studies in rats.


Assuntos
Cromatografia Líquida/métodos , Oxazepinas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Oxazepinas/química , Oxazepinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
J Chromatogr Sci ; 51(6): 517-23, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23135133

RESUMO

A method for assaying a novel phosphodiesterase-4 inhibitor, 2-aryl-7(3',4'-dialkoxyphenyl)-pyrazolo [1,5-alpha] pyrimidine (PDE-310), was developed and validated in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Rat plasma samples were processed by liquid-liquid extraction with ethyl acetate and injected onto the LC-MS-MS system for quantification. PDE-310 and imipramine (i.e., internal standard) were separated using a Gemini C18 column with mixture of acetonitrile and 0.1% formic acid (70:30, v/v) as the mobile phase. The ion transitions monitored were m/z 425.0 → 331.0 for PDE-310 and m/z 281.3 → 86.1 for imipramine in the multiple-reaction monitoring mode. The detector response was specific and linear for PDE-310 concentrations in the range of 0.1-50 µg/mL. The intra-day and inter-day precision and accuracy of the method were determined to be within the acceptance criteria for assay validation guidelines. The recoveries were approximately 85.7 and 88.2% from rat plasma for PDE-310 and imipramine, respectively. PDE-310 was stable under various processing and handling conditions. PDE-310 concentrations were readily measured in rat plasma samples up to 8 h after an intravenous administration of PDE-310, suggesting that the assay is practically useful.


Assuntos
Cromatografia Líquida/métodos , Inibidores da Fosfodiesterase 4/sangue , Pirazóis/sangue , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Pirazóis/química , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
9.
Xenobiotica ; 43(2): 193-200, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22856387

RESUMO

This study evaluated the pharmacokinetics of the novel TAZ modulator TM-25659 in rats following intravenous and oral administration at dose ranges of 0.5-5 mg/kg and 2-10 mg/kg, respectively. Plasma protein binding, plasma stability, liver microsomal stability, CYP inhibition, and transport in Caco-2 cells were also evaluated. After intravenous injection, systemic clearance, steady-state volumes of distribution, and half-life were dose-independent, with values ranging from 0.434-0.890 mL · h(-1) · kg(-1), 2.02-4.22 mL/kg, and 4.60-7.40 h, respectively. Mean absolute oral bioavailability was 50.9% and was not dose dependent. Recovery of TM-25659 was 43.6% in bile and <1% in urine. In pharmacokinetic modeling studies, the three-compartment (3C) model was appropriate for understanding these parameters in rats. TM-25659 was stable in plasma. Plasma protein binding was approximately 99.2%, and was concentration-independent. TM-25659 showed high permeation of Caco-2 cells and did not appear to inhibit CYP450. TM-25659 was metabolized in phase I and II steps in rat liver microsomes. In conclusion, the pharmacokinetics of TM-25659 was characterized for intravenous and oral administration at doses of 0.5-5 and 2-10 mg/kg, respectively. TM-25659 was eliminated primarily by hepatic metabolism and urinary excretion.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Algoritmos , Animais , Proteínas Sanguíneas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Células CACO-2 , Inibidores das Enzimas do Citocromo P-450 , Interações Medicamentosas , Humanos , Injeções Intravenosas , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Cinética , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Tetrazóis/administração & dosagem , Tetrazóis/sangue , Fatores de Transcrição
10.
J Pharm Biomed Anal ; 70: 587-91, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22738786

RESUMO

FK-3000 can inhibit proliferation of carcinomas and arrest the growth of carcinoma cells through cytotoxic (apoptosis induction) and cytostatic (cell cycle arrest) effects. A rapid and sensitive assay was developed and validated using liquid chromatography-mass spectrometry (LC-MS) for FK-3000 in rat plasma. FK-3000 was extracted with ethyl acetate from rat plasma samples, and the residue containing the FK-3000 was dried in a gentle stream of nitrogen and reconstituted with acetonitrile. The FK-3000 was quantified using high-performance liquid chromatography (HPLC; Waters Alliance 2695) with a reversed phase Gemini column (3 mm × 150 mm, 5 µm; Phenomenex, USA) and a Waters Micromass ZQ detector. FK-3000 and phenazine, an internal standard (IS), were analyzed by selected ion monitoring (SIM) at m/z transitions of 418.45 and 256, respectively. A lower limit of quantification (LLOQ) of 10 ng/mL was observed, with a linear dynamic range from 10 to 10,000 ng/mL (R>0.999). The accuracy, precision, recovery, matrix effects, and stability of the assay were deemed acceptable according to the FDA guidance for industry (bioanalytical method validation). The FK-3000 concentration was measured in plasma samples up to 6 h following FK-3000 administration at an oral dose of 20 mg/kg. The findings indicate that the assay method is suitable for routine pharmacokinetic (PK) studies of FK-3000 in rats.


Assuntos
Alcaloides/sangue , Alcaloides/farmacocinética , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Espectrometria de Massas por Ionização por Electrospray , Acetatos/química , Acetonitrilos/química , Administração Oral , Alcaloides/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Calibragem , Cromatografia Líquida de Alta Pressão/normas , Cromatografia de Fase Reversa/normas , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/normas
11.
J Pharm Sci ; 101(3): 1302-13, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22147445

RESUMO

The objectives of this study were to investigate the allele frequencies and linkage disequilibrium (LD) in the organic anion transporting polypeptide 1B3 (OATP1B3) in the Korean population and to examine the functional consequences. Using samples from 48 Koreans, direct sequencing was carried out to determine the allele frequencies and LD of OATP1B3 in a representative Korean population. Thirty-six genetic variations in the transporter were found in Koreans; among them, five undocumented variations (i.e.,-6436G>C in the 5'-upstream region, 26A>C and 586A>G in the protein coding region, and IVS6-72A>T and IVS12-80A>T in intron regions) were identified. In the upstream region, -5035G>A was found to have lowered gene expression, as determined by a reporter gene assay, suggesting that this variation reduces the expression of OATP1B3 in humans. The functional relevance of the genetic variations in the protein coding region was determined by an uptake study involving representative substrates in human embryonic kidney 293 cells expressing wild type or variant forms. Variations involving 699G>A showed a reduced uptake activity for testosterone, but not for estradiol 17ß-d-glucuronide or methotrexate, indicating that the functional impact of the variations is substrate specific. Considering the kinetic relevance of OATP1B3, the functionally affected variations may be therapeutically important.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Frequência do Gene , Desequilíbrio de Ligação , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Adulto , Sequência de Bases , Linhagem Celular , Variação Genética , Humanos , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Farmacogenética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Adulto Jovem
12.
Xenobiotica ; 41(12): 1100-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21838595

RESUMO

This study aimed to characterise the pharmacokinetics of lurasidone, a new atypical anti-psychotic drug, in rats after intravenous and oral administration at dose range 0.5-2.5 and 2.5-10 mg/kg, respectively. Moreover, tissue distribution, liver microsomal stability and plasma protein binding were estimated. After intravenous injection, systemic clearance, steady-state volumes of distribution and half-life remained unaltered as a function of dose with values in the range 22.1-27.0 mL/min/kg, 2,380-2,850 mL/kg and 229-267 min, respectively. Following oral administration, absolute oral bioavailability was not dose dependent with approximately 23%. The recoveries of lurasidone in urine and bile were 0.286% and 0.0606%, respectively. Lurasidone was primarily distributed to nine tissues (brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose) and tissue-to-plasma ratios of lurasidone were ranged from 1.06 (brain) to 9.16 (adipose). Further, lurasidone was unstable in rat liver microsome and the plasma protein binding of lurasidone was concentration independent with approximately 99.6%. In conclusion, lurasidone showed dose-independent pharmacokinetics at an intravenous dose of 0.5-2.5 mg/kg and an oral dose of 2.5-10 mg/kg. Lurasidone was primarily distributed to nine tissues and appeared to be primarily eliminated by its metabolism.


Assuntos
Antipsicóticos/farmacocinética , Isoindóis/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Antipsicóticos/química , Injeções Intravenosas , Isoindóis/administração & dosagem , Isoindóis/sangue , Isoindóis/química , Cloridrato de Lurasidona , Masculino , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Tiazóis/administração & dosagem , Tiazóis/sangue , Tiazóis/química
13.
J Pharmacokinet Pharmacodyn ; 38(5): 637-51, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21866408

RESUMO

The objective of this study was to characterize the systemic and tissue kinetics of 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl) benzofuran (SNU-0039), an inhibitor of ß-amyloid protein aggregation, in rats. Simultaneous fitting of the data to polyexponential equations indicated that the systemic clearance and steady state volume of distribution were estimated to be 0.0220 l/min/kg and 2.33 l/kg. The clearance and volume of distribution were not dependent on the intravenous dose, in the range from 5 to 20 mg/kg. The tissue (i.e., the brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose tissue) to plasma partition coefficients (K(p)) for SNU-0039 in rats ranged from a low of 0.779 ± 0.314 (muscle) to a high of 5.71 ± 1.66 (liver). The recoveries of DMB were less than 1% of the dose for the renal and biliary excretion, indicative of minor involvements of these pathways in overall elimination. The fraction of bound SNU-0039 to plasma protein was approximately 95.9% and the fraction of SNU-0039 distributed to blood cells was approximately 45.3%. Assuming a flow-limited distribution, the simulated concentration profiles for SNU-0039 in the physiologically based pharmacokinetic model were in reasonable agreement with the observed concentrations in plasma and nine tissues in rats.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacocinética , Simulação por Computador , Nootrópicos/farmacocinética , Doença de Alzheimer/metabolismo , Animais , Benzofuranos/administração & dosagem , Benzofuranos/sangue , Injeções Intravenosas , Rim/metabolismo , Fígado/metabolismo , Masculino , Músculos/metabolismo , Nootrópicos/administração & dosagem , Nootrópicos/sangue , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Baço/metabolismo , Distribuição Tecidual
14.
Drug Dev Ind Pharm ; 37(12): 1394-401, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21702739

RESUMO

A single-dose glass ampoule was developed for ease of administration. When glass ampoules are opened, resulting in contamination by particulate matter. Reducing its contamination may minimize the risk in patients due to particulates. This study reports on an attempt to reduce insoluble particulate contamination by developing methods for the precise measurement of this. A vacuum machine (VM) was used to reduce the level of insoluble particulate contamination, and a microscopy, scanning electron microscopy-energy dispersive X-ray spectrometer (SEM-EDS) and inductively coupled plasma-atomic emission spectrometer (ICP-AES) were used to evaluate the level of reduction. The method permitted the insoluble particle content to be reduced by up to 87.8 and 89.3% after opening 1 and 2 mL-ampoules, respectively. The morphology of the glass particulate contaminants was very sharp and rough, a condition that can be harmful to human health. The total weight of glass particles in the opened ampoules was determined to be 104 ± 72.9 µg and 30.5 ± 1.00 µg after opening 1 and 2 mL-ampoules when the VM was operated at highest power. The total weights were reduced to 53.6 and 50.6%, respectively for 1 and 2 mL-ampoules, compared to opening by hand. The loss of ampoule contents on opening by the VM was 6.50 and 4.67% for 1 and 2 mL-ampoules, respectively. As a result, the VM efficiently reduced glass particulate contamination and the evaluation methods used were appropriate for quantifying these levels of contamination.


Assuntos
Contaminação de Medicamentos/prevenção & controle , Embalagem de Medicamentos/métodos , Vidro , Embalagem de Medicamentos/normas , Humanos , Injeções , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Soluções Farmacêuticas , Espectrometria por Raios X/métodos , Espectrofotometria Atômica/métodos
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