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1.
Mar Drugs ; 18(6)2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32512874

RESUMO

Scytonemin is a yellow-green ultraviolet sunscreen pigment present in different genera of aquatic and terrestrial blue-green algae, including marine cyanobacteria. In the present study, the anti-inflammatory activities of scytonemin were evaluated in vitro and in vivo. Topical application of scytonemin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear swelling in BALB/c mice. The expression of tumor necrosis factor-a (TNF-a) and inducible nitric oxide synthase (iNOS) was also suppressed by scytonemin treatment in the TPA-treated ear of BALB/c mice. In addition, scytonemin inhibited lipopolysaccharide (LPS)-induced production of TNF-a and nitric oxide (NO) in RAW 264.7 cells, a murine macrophage-like cell line, and the mRNA expressions of TNF-a and iNOS were also suppressed by scytonemin in LPS-stimulated RAW 264.7 cells. Further study demonstrated that LPS-induced NF-kB activity was significantly suppressed by scytonemin treatment in RAW 264.7 cells. Our results also showed that the degradation of IkBa and nuclear translocation of the p65 subunit were blocked by scytonemin in LPS-stimulated RAW 264.7 cells. Collectively, these results suggest that scytonemin inhibits skin inflammation by blocking the expression of inflammatory mediators, and the anti-inflammatory effect of scytonemin is mediated, at least in part, by down-regulation of NF-kB activity. Our results also suggest that scytonemin might be used as a multi-function skin care ingredient for UV protection and anti-inflammation.

2.
Pharmaceutics ; 12(5)2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32357395

RESUMO

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 µM, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min∙µg/mL vs. 25.7 ± 9.98 min∙µg/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food-drug interactions should be considered.

3.
Int J Mol Sci ; 21(7)2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32260456

RESUMO

Tacrolimus is an immunosuppressive drug with a narrow therapeutic index and larger interindividual variability. We identified genetic variants to predict tacrolimus exposure in healthy Korean males using machine learning algorithms such as decision tree, random forest, and least absolute shrinkage and selection operator (LASSO) regression. rs776746 (CYP3A5) and rs1137115 (CYP2A6) are single nucleotide polymorphisms (SNPs) that can affect exposure to tacrolimus. A decision tree, when coupled with random forest analysis, is an efficient tool for predicting the exposure to tacrolimus based on genotype. These tools are helpful to determine an individualized dose of tacrolimus.

4.
J Pharm Biomed Anal ; 179: 112987, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31761376

RESUMO

Motolimod (VTX-2337) is an agonist of toll-like receptor 8. In this study, a novel and sensitive liquid chromatography-tandem mass spectrometry method was developed for quantifying motolimod in rat plasma and subsequently used in a pharmacokinetic study. Proteins were precipitated from plasma samples using acetonitrile prior to the analysis. GS-9620 was used as an internal standard. High-performance liquid chromatography was performed using a Spursil C18-EP column (3 µm, 50 × 2.1 mm). Aqueous ammonium formate and acetonitrile were used as the mobile phase. Motolimod was detected using an electrospray ionization interface under multiple reaction monitoring conditions in the positive ion mode. The developed method produced a linear correlation over a concentration range of 1-1000 ng/mL (r = 0.9944). Intra- and inter-day precision values ranged from 4.8%-10.7% (the lower limit of quantification precision value was 16.3 %), whereas intra- and inter-day accuracy values ranged from 0.3%-9.1 %. The mean recovery of motolimod from rat plasma was 109.4 %. Additionally, motolimod was found to be stable under various conditions (three freeze-thaw cycles, 6-h storage at room temperature, short- and long-term stability tests, and processing). The developed method was successfully used in a pharmacokinetic study in rats. Motolimod showed non-linear pharmacokinetics following its intravenous administration to rats at 0.6-6 mg/kg. Additionally, very low exposure (<1 %) was obtained following oral administration of the drug to rats. The results also showed that motolimod has a low metabolic stability in the liver microsomes and exhibits extensive binding to the plasma proteins.

5.
Chemosphere ; 239: 124751, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31518922

RESUMO

Bisphenol A (BPA) is a chemical monomer widely used in the production of hard plastics for food containers and personal items. Through improper industrial control and disposal, BPA has become a pervasive environmental contaminant, and toxicological studies have shown potent xenobiotic endocrine disruptor activity. Prenatal exposure in particular can lead to infertility and nervous system disorders characterized by behavioral aggression, depression, and cognitive impairment, thus necessitating careful hazard assessment. In this study, we evaluated BPA accumulation rate, blood-brain barrier (BBB) permeability, lethality, cardiotoxicity, behavioral effects, and impacts on multiple neurochemical pathways in zebrafish larvae. The bioconcentration factor (BCF) ranged from 1.95 to 10.0, resulting in a high rate of accumulation in the larval body. Also, high BBB permeability allowed BPA to accumulate at similar rates in both zebrafish and adult mouse (blood to brain concentration ratios of 3.2-6.7 and 1.8 to 5.5, respectively). In addition, BPA-exposed zebrafish larvae exhibited developmental deformities, reduced heart rate, and impaired behavioral patterns, including decreased total distance traveled, slower movement velocity, and altered color-preference. These impairments were associated with inhibition of the phenylalanine to dopamine synthesis pathway and an imbalance between excitatory and inhibitory neurotransmitter systems. Our results suggest that behavioral alteration in BPA-exposed zebrafish result from high accumulation and ensuing dysregulation of serotonergic, kynurenergic, dopaminergic, cholinergic, and GABAergic neurotransmitter systems. In conclusion, similarities in toxic responses to mammalian models highlight the utility of the zebrafish larva as a convenient model for screening environmental toxins.


Assuntos
Comportamento Animal/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Barreira Hematoencefálica/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Neurotransmissores/metabolismo , Fenóis/toxicidade , Peixe-Zebra/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Larva/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Testes de Toxicidade Aguda , Poluentes Químicos da Água/toxicidade
6.
Eur J Pharm Sci ; 130: 1-10, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30641142

RESUMO

A physiologically-based pharmacokinetic (PBPK) model was developed for YH4808, a novel potassium-competitive acid blocker, using the SimCYP® Simulator based on the physicochemical, in vitro preclinical and clinical data of YH4808. The PBPK model was optimized using YH4808 concentrations obtained from the single-dose phase I clinical trial. Overall, the PBPK model adequately predicted the observed pharmacokinetic profiles of YH4808 in humans. The pharmacokinetic profiles of YH4808 after multiple oral administrations were predicted using a refined PBPK model. The ratios of model-predicted to observed Cmax, AUCinf and AUCτ values on Day 1 and Day 7 at 100 mg were 0.7-1.0. However, the model failed to predict a decreased exposure after multiple oral administration particularly at higher doses of 200 and 400 mg. The reduced solubility of YH4808 at higher pH was hypothesized as the main cause of the reduction in exposure such that absorption was decreased as pH was increased. This hypothesis was confirmed by PBPK modeling and simulation, where intragastric pH was increased by YH4808.


Assuntos
Antiácidos/administração & dosagem , Antiácidos/farmacocinética , Esomeprazol/análogos & derivados , Modelos Biológicos , Administração Oral , Adulto , Animais , Células CACO-2 , Cães , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esomeprazol/administração & dosagem , Esomeprazol/farmacocinética , Haplorrinos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Adulto Jovem
7.
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
8.
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
9.
Drug Metab Dispos ; 47(2): 94-103, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30504137

RESUMO

We investigated whether human serum albumin (HSA) in suspended human hepatocytes would affect the uptake clearance of anionic drugs with high binding to HSA and improve the extrapolation of in vivo hepatic clearance from in vitro uptake clearance by the hepatocytes via the "albumin-mediated" hepatic uptake mechanism. The uptake clearances for total forms (PS inf) and for unbound forms (PS u,inf) of 11 anionic drugs [all of which were organic anion-transporting polypeptide (OATP) substrates] were determined with suspended human hepatocytes in varying concentrations of HSA. The fraction of unbound drugs (f u) was determined using an equilibrium dialysis at the various HSA concentrations. The PS inf values decreased with increasing concentrations of HSA, whereas the unbound uptake clearances (PS u,inf(+) = PS inf/ f u) in the presence of HSA increased substantially, thus demonstrating the "albumin-mediated" hepatic uptake mechanism. The relationships between PS inf and HSA concentration were well described by the previously proposed facilitated-dissociation model, in which the drug-albumin complex interacts with the cell surface, enhancing the dissociation of the complex and providing unbound drug for hepatic uptake. Furthermore, the PS u,inf (+) values in in vivo conditions (at 5% HSA) were predicted from those obtained in isolated hepatocytes on the basis of the facilitated-dissociation model, revealing compatibility with the overall hepatic intrinsic clearance in vivo. We conclude that the "facilitated-dissociation" model is useful for describing the "albumin-mediated" hepatic uptake phenomenon of OATP drugs and to predict hepatic uptake clearance in vivo.


Assuntos
Eliminação Hepatobiliar , Hepatócitos/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Albumina Sérica Humana/metabolismo , Ânions/metabolismo , Humanos , Transportadores de Ânions Orgânicos/metabolismo , Plasma/metabolismo , Ligação Proteica
10.
J Pharm Biomed Anal ; 151: 61-70, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29306735

RESUMO

We previously reported that MDR-1339, an inhibitor of ß-amyloid protein aggregation, was likely to be eliminated by biotransformation in rats. The objective of this study was to determine the chemical identity of metabolites derived from this aggregate inhibitor and to characterize the kinetics of formation of these metabolites in rats. Using high performance liquid chromatography coupled with mass spectrometry with a hybrid triple quadrupole-linear ion trap, 7 metabolites and 1 potential metabolic intermediate were identified in RLM incubations containing MDR-1339. In addition to these, 3 glucuronide metabolites were detected in urine samples from rats receiving a 10 mg/kg oral dose of MDR-1339. When the kinetics of the formation of two major metabolites, M1 and M2, were analyzed assuming simple Michaelis-Menten kinetics, the Vmax and Km values were found to be 0.459 ±â€¯0.0196 nmol/min/mg protein and 28.3 ±â€¯3.07 µM for M1, and 0.101 ±â€¯0.00537 nmol/min/mg protein and 14.7 ±â€¯2.37 µM for M2, respectively. When chemically synthesized M1 and M2 were individually administered to rats intravenously at the dose of 5 mg/kg respectively, the volume of distribution and elimination clearance were determined to be 4590 ±â€¯709 mL/kg and 68.4 ±â€¯5.60 mL/min/kg for M1 and 15300 ±â€¯8110 mL/kg and 98.0 ±â€¯19.5 mL/min/kg for M2, respectively. When MDR-1339 was intravenously administered to rats at a dose of 5 mg/kg, the parent drug and M1 were readily detected for periods of up to 6 h after the administration, but M2 was observed only from 2 to 4 h. A standard moment analysis indicates that the formation clearance of M1 is 6.01 mL/min/kg, suggesting that 19.7% of the MDR-1339 dose was eliminated in rats. These observations indicate that the hepatic biotransformation of MDR-1339 results in the formation of at least 10 metabolites and that M1 is the major metabolite derived from this aggregation inhibitor in rats.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/metabolismo , Microssomos Hepáticos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Animais , Benzofuranos/farmacologia , Relação Dose-Resposta a Droga , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Agregados Proteicos/fisiologia , Ratos , Ratos Sprague-Dawley
11.
Drug Metab Dispos ; 46(3): 259-267, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29298773

RESUMO

The effects of bovine serum albumin and human serum albumin on the unbound hepatic uptake clearance (PSu,inf) of the organic anion-transporting polypeptide substrates 1-anilino-8-naphthalene sulfonate (ANS) and pitavastatin (PTV) were determined using primary cultured rat hepatocytes and isolated human hepatocytes, respectively. The PSu,inf value of hepatocytes was estimated by dividing the initial uptake rate of these anions by their unbound concentrations. The PSu,inf values for ANS and PTV were enhanced in the presence of albumin, thereby demonstrating the phenomenon of "albumin-mediated" hepatic uptake. We previously constructed a "facilitated-dissociation" model, in which the interaction of the ligand-albumin complex with the cell surface enhanced the dissociation of that complex to provide unbound ligand for uptake to the hepatocytes [J Pharmacokinet Biopharm 16:165-181 (1988)]. That model was able to describe accurately the relationship between the enhancement of the PSu,inf values and the albumin concentration. By considering the enhancement of hepatic uptake clearance by albumin using this facilitated-dissociation model, we could predict accurately the PSu,inf in vivo from that obtained in isolated hepatocytes. In the light of these findings, we suggest that the facilitated-dissociation model is applicable to describing the phenomenon of albumin-mediated hepatic uptake via organic anion transporters and to evaluating hepatic uptake clearance in vivo.


Assuntos
Albuminas/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Naftalenossulfonato de Anilina/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Humanos , Cinética , Fígado/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
12.
Xenobiotica ; 48(8): 831-838, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28803538

RESUMO

1. We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3-3 mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined. 2. After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (Vss) and half-life (T½) remained unaltered as a function of dose, with values in the ranges of 6.41-7.03 mL/h/kg, 270-354 mL/kg and 39.5-46.9 h, respectively. Following oral administration, absolute bioavailability was 99.7-104% and was independent of doses from 0.3 to 3 mg/kg. In the urine and faeces, 4.36% and 48.9% of tafamidis, respectively, were recovered. 3. Tafamidis was distributed primarily in the liver and not in the brain, kidney, testis, heart, spleen, lung, gut, muscle, or adipose tissue. Further, tafamidis was very stable in rat liver microsomes, and its plasma protein binding was 99.9%. 4. In conclusion, tafamidis showed dose-independent pharmacokinetics with intravenous and oral doses of 0.3-3 mg/kg. Tafamidis undergoes minimal first-pass metabolism, distributes mostly in the liver and plasma, and appears to be eliminated primarily via biliary excretion.


Assuntos
Neuropatias Amiloides Familiares , Benzoxazóis/farmacologia , Benzoxazóis/farmacocinética , Encéfalo/metabolismo , Fígado/metabolismo , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/patologia , Animais , Encéfalo/patologia , Células CACO-2 , Humanos , Fígado/patologia , Masculino , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/patologia , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley
13.
Zebrafish ; 14(4): 322-330, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28488933

RESUMO

The objective of this study was to evaluate the permeability of small molecules into the brain via the blood-brain barrier in zebrafish and to investigate the possibility of using this animal model as a screening tool during the early stages of drug discovery. Fifteen compounds were used to understand the permeation into the brain in zebrafish and mice. The ratio of brain-to-plasma concentration was compared between the two animal models. The partition coefficient (Kp,brain), estimated using the concentration ratio at designated times (0.167, 0.25, 0.5, or 2 h) after oral administrations (per os, p.o), ranged from 0.099 to 5.68 in zebrafish and from 0.080 to 11.8 in mice. A correlation was observed between the Kp,brain values obtained from the zebrafish and mice, suggesting that zebrafish can be used to estimate Kp,brain to predict drug penetration in humans. Furthermore, in vivo transport experiments to understand the permeability glycoprotein (P-gp) transporter-mediated behavior of loperamide (LPM) in zebrafish were performed. The zebrafish, Kp,brain,30min of LPM was determined to be 0.099 ± 0.069 after dosing with LPM alone, which increased to 0.180 ± 0.115 after dosing with LPM and tariquidar (TRQ, an inhibitor of P-gp). In mouse, the Kp,brain,30min of LPM was determined to be 0.080 ± 0.004 after dosing with LPM alone and 0.237 ± 0.013 after dosing with LPM and TRQ. These findings indicate that the zebrafish could be used as an effective screening tool during the discovery stages of new drugs to estimate their distribution in the brain.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Loperamida/farmacologia , Modelos Animais , Quinolinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Antidiarreicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Peixe-Zebra
14.
Drug Metab Dispos ; 45(3): 246-259, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28069721

RESUMO

Cytochrome P450 enzymes and human organic anion transporting polypeptide (OATP) 1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new peroxisome proliferator-activated receptor γ agonist. Atorvastatin (ATV), a substrate for CYP3A and human OATP1B1, is likely to be coadministered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was administered intravenously with ATV, the systemic clearance and volume of distribution at steady state for LB remained unchanged (2.67 ± 0.63 ml/min per kg and 289 ± 20 ml/kg, respectively), compared with that of LB without ATV (2.34 ± 0.37 ml/min per kg and 271 ± 20 ml/kg, respectively). Although the tissue-to-plasma partition coefficient (Kp) of LB was not affected by ATV in most major tissues, the liver Kp for LB was decreased by ATV coadministration. Steady-state liver Kp values for three levels of LB were significantly decreased as a result of ATV coadministration. LB uptake was inhibited by ATV in rat OATP1B2-overexpressing Madin-Darby canine kidney cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a physiologically based pharmacokinetics model, the characteristics of LB distribution to the liver were consistent with the findings of the in vivo study. It thus appears that the distribution of LB to the liver is mediated by the hepatic uptake of transporters such as rat OATP1B2, and carrier-mediated transport is involved in the liver-specific drug-drug interaction between LB and ATV in vivo.


Assuntos
Atorvastatina/farmacologia , Fígado/metabolismo , Pirimidinas/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Tiazolidinedionas/farmacocinética , Animais , Atorvastatina/sangue , Transporte Biológico , Cães , Relação Dose-Resposta a Droga , Interações Medicamentosas , Injeções Intravenosas , Células Madin Darby de Rim Canino , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Pirimidinas/sangue , Ratos Sprague-Dawley , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Especificidade por Substrato , Tiazolidinedionas/sangue , Distribuição Tecidual , Transfecção
15.
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
16.
Arch Pharm Res ; 38(11): 2076-82, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25956695

RESUMO

We characterized the pharmacokinetics of enzalutamide, a novel anti-prostate cancer drug, in rats after intravenous and oral administration in the dose range 0.5-5 mg/kg. Tissue distribution, liver microsomal stability, and plasma protein binding were also examined. After intravenous injection, systemic clearance, volumes of distribution at steady state (Vss), and half-life (T½) remained unaltered as a function of dose, with values in the ranges of 80.4-86.3 mL/h/kg, 1020-1250 mL/kg, and 9.13-10.6 h, respectively. Following oral administration, absolute oral bioavailability was 89.7 % and not dose-dependent. The recoveries of enzalutamide in urine and feces were 0.0620 and 2.04 %, respectively. Enzalutamide was distributed primarily in 10 tissues (brain, liver, kidneys, testis, heart, spleen, lungs, gut, muscle, and adipose) and tissue-to-plasma ratios of enzalutamide ranged from 0.406 (brain) to 10.2 (adipose tissue). Further, enzalutamide was stable in rat liver microsomes, and its plasma protein binding was 94.7 %. In conclusion, enzalutamide showed dose-independent pharmacokinetics at intravenous and oral doses of 0.5-5 mg/kg. Enzalutamide distributed primarily to 10 tissues and appeared to be eliminated primarily by metabolism.


Assuntos
Antineoplásicos/farmacocinética , Microssomos Hepáticos/metabolismo , Feniltioidantoína/análogos & derivados , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Meia-Vida , Injeções Intravenosas , Masculino , Feniltioidantoína/administração & dosagem , Feniltioidantoína/farmacocinética , Neoplasias da Próstata/tratamento farmacológico , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
17.
Oncotarget ; 5(20): 10180-97, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25338206

RESUMO

As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Corantes Fluorescentes/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Xantinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Chem Res Toxicol ; 27(1): 34-41, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24304388

RESUMO

Inflammation plays a critical defensive role in the human body. However, uncontrolled or aberrant inflammatory responses contribute to various acute and chronic diseases. The Nrf2-ARE pathway plays a pivotal role in the regulation of inflammatory markers, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). On the basis of this concept, we synthesized a novel anti-inflammatory 4,6-bis ((E)-4-hydroxy-3-methoxystyryl)-1-phenethylpyrimidine-2(1H)-thione (HPT), and in vitro experiments using HepG2-C8 ARE-luciferase-transfected cells demonstrated the induction of Nrf2-ARE activity. In lipopolysaccharide (LPS)-induced RAW 264.7 cells, HPT treatment reduced the production of nitric oxide (NO) as well as the protein and mRNA expression levels of COX-2 and iNOS, in a dose-dependent manner. In addition, HPT suppressed the mRNA expression of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6. In LPS-induced macrophages, HPT inhibited COX-2 and iNOS by blocking the activation of p38 and c-Jun NH2-terminal kinase (JNK) but not extracellular signal-regulated kinase (ERK1/2). Furthermore, an in vivo anti-inflammatory study was performed using a TPA-induced skin inflammation mouse model, and the results showed that HPT reduced TPA-induced inflammation and attenuated the expression of COX-2 and iNOS in TPA-induced mouse skin tissue. Thus, HPT demonstrated anti-inflammatory activity both in LPS-induced RAW 264.7 cells and TPA-stimulated mouse skin and may therefore serve as a potential anti-inflammatory agent.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Pirimidinas/farmacologia , Tionas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células Hep G2 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Pirimidinas/química , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/antagonistas & inibidores , Tionas/química , Células Tumorais Cultivadas
19.
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
20.
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
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