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1.
Int J Nanomedicine ; 14: 3943-3953, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239664

RESUMO

Background: SKLB023, a novel 5-benzylidenethiazolidine-2,4-dione based-derivative, specifically inhibits inducible nitric oxide synthase and shows promise for treating non-alcoholic steatohepatitis (NASH). However, its poor water solubility and low bioavailability limits its clinical use. Here the drug was loaded into phosphatidylcholine-bile salt-mixed micelles (PBMM/SKLB023) to overcome these limitations. Methods: PBMM/SKLB023 was developed using a simple co-precipitation method, and formulation parameters were optimized. The pharmacokinetics of PBMM/SKLB023 were investigated in Wistar rats, and therapeutic efficacy was assessed in a mouse model of NASH induced by a diet deficient in methionine- and choline. Results: PBMM/SKLB023 particles were 11.36±2.08 nm based on dynamic light scattering, and loading the drug into micelles improved its water solubility 300-fold. PBMM/SKLB023 inhibited proliferation and activation of HSC-T6 cells more strongly than free SKLB023. PBMM/SKLB023 showed longer mean retention time and higher bioavailability than the free drug after intravenous injection in Wistar rats. In the mouse model of NASH, PBMM/SKLB023 alleviated hepatic lipid accumulation, inflammation, and fibrosis to a significantly greater extent than free SKLB023. Conclusion: PBMM/SKLB023 shows therapeutic potential for treating NASH and liver fibrosis.


Assuntos
Acetanilidas/uso terapêutico , Micelas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Acetanilidas/sangue , Acetanilidas/química , Acetanilidas/farmacocinética , Animais , Ácidos e Sais Biliares/química , Modelos Animais de Doenças , Inflamação/patologia , Injeções Intravenosas , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/química , Ratos Wistar , Solubilidade , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética
2.
Artigo em Inglês | MEDLINE | ID: mdl-31082683

RESUMO

Thiazolidinediones and quinazolin-4-ones compounds, previously known for their activity against Type 2 diabetes and antifungal activity respectively, are currently being investigated for their anti-cancer activity. The determination of pharmacokinetic parameters for these two classes of compounds using a simultaneous chromatographic method with a low detection limit is a challenge. In this study, a highly sensitive and simultaneous LC-MS/MS-based bioanalytical method was developed and validated in rat plasma for the estimation of four novel anti-cancer compounds, BIT-15-67 and BNT-11, belonging to the Thiazolidinedione class, and BNUA-108 and BNUA-48, from the quinazolin-4-one class. The analytes were extracted from plasma samples by protein precipitation and separated on a short reverse phase Hypersil Phenyl BDS, 50 × 4.6 mm, 2.4 µm column at a column oven temperature of 40 °C. An isocratic mobile phase, a 20:80 (v/v) mixture of 5 mM ammonium acetate solution and acetonitrile containing 0.1% formic acid, was used for the elution at a flow rate of 0.4 mL/min. The analytes and internal standard, sulfaphenazole, were quantified in the multiple reaction monitoring mode using positive electrospray ionization with specific pair of mass by charge ratio. All standard validation parameters were assessed as per current bioanalytical method validation guidelines in rat plasma. The area response for the four analytes was found to be linear over the concentration range of 1.00 to 1000 ng/mL in rat plasma. The signal to noise at LLOQ of 1 ng/mL was adequate for application to different pre-clinical studies. The intra- and inter-day precision were <11% and accuracy deviated -1.8 to 9.60% from the nominal. The mean recovery was high (about 90%) and consistent for all the analytes over the linear dynamic range of the method. This simple, robust and validated method can be employed to determine the rat plasma concentrations of the four selected anticancer compounds in preclinical studies such as the pharmacodynamic and the pharmacokinetic studies including tissue distribution and excretion, and the toxicokinetic studies. In this study, pharmacokinetic parameters were determined using this method for all the four compounds individually following intravenous administration in rats.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Quinazolinonas/sangue , Espectrometria de Massas em Tandem/métodos , Tiazolidinedionas/sangue , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética
3.
Int J Clin Pharmacol Ther ; 56(9): 426-433, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29932413

RESUMO

OBJECTIVE: This study was conducted to evaluate the pharmacokinetics and bioequivalence of two formulations of -DuvieTM (0.5-mg lobeglitazone sulfate). MATERIALS AND METHODS: This study was designed as an open-label, randomized, single-dose, crossover bioequivalence study in healthy male subjects. A total of 28 subjects were randomized into two groups: one group received the test drug, 0.5-mg DuvieTM tablets, which have formulations available on the global market; and the other group received the reference drug, the initially-approved 0.5-mg DuvieTM tablets. Plasma samples were collected for up to 48 hours after drug treatment and were analyzed for lobeglitazone using validated liquid chromatography-tandem mass spectrometry. Individual pharmacokinetic properties were determined by noncompartmental methods. Safety assessments were performed. RESULTS: 28 subjects completed the study and were included in the pharmacokinetic analysis. The mean (standard deviation) values of -AUClast for the test and reference formulations were 367.49 (157.92) and 362.40 (140.05) ng×h/mL, respectively. The mean (standard deviation) values of Cmax for the test and reference formulations were 50.35 (6.94) and 49.29 (6.71) ng/mL, respectively. The 90% confidence intervals for AUClast and Cmax were 0.9150 - 1.1088 and 0.9879 - 1.0561, respectively. All adverse events were mild, and there were no serious adverse events. CONCLUSION: This study suggests that the two lobeglitazone tablet formulations have similar exposure and absorption rates. Therefore, the newly-developed formulation of the 0.5-mg DuvieTM tablet is expected to contribute to the treatment of patients with type 2 diabetes.
.


Assuntos
Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Composição de Medicamentos , Meia-Vida , Voluntários Saudáveis , Humanos , Hipoglicemiantes/sangue , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Pirimidinas/sangue , República da Coreia , Espectrometria de Massas por Ionização por Electrospray , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Tiazolidinedionas/sangue , Adulto Jovem
4.
Pharmacol Res Perspect ; 6(2): e00327, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29545948

RESUMO

This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively. Additionally, this study assessed the effect of a weak CYP2C8 inhibitor, trimethoprim, as a perpetrator of a DDI with daprodustat. This was a two-part study: Part A assessed the effect of coadministration of daprodustat on the pharmacokinetics of pioglitazone and rosuvastatin in 20 subjects; Part B assessed the coadministration of trimethoprim on the pharmacokinetics of daprodustat in 20 subjects. Coadministration of 100 mg of daprodustat with pioglitazone or rosuvastatin had no effect on the plasma exposures of either probe substrate. When trimethoprim was coadministered with 25-mg daprodustat plasma daprodustat AUC and Cmax increased by 48% and 28%, respectively. Additionally, AUC and Cmax for the metabolite GSK2531401 were decreased by 32% and 40%, respectively. Cmax for the other metabolites was slightly decreased (~8-15%) but no changes in AUC were observed. As 100-mg daprodustat exceeds the planned top therapeutic dose, interaction potential of daprodustat as a perpetrator with substrates of the CYP2C8 enzyme and OATP1B1 transporters is very low. Conversely, daprodustat exposure (AUC and Cmax) is likely to increase moderately with coadministration of weak CYP2C8 inhibitors.


Assuntos
Barbitúricos/farmacologia , Citocromo P-450 CYP2C8/metabolismo , Glicina/análogos & derivados , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Rosuvastatina Cálcica/sangue , Tiazolidinedionas/sangue , Trimetoprima/sangue , Administração Oral , Barbitúricos/administração & dosagem , Barbitúricos/sangue , Estudos Cross-Over , Interações de Medicamentos , Feminino , Glicina/administração & dosagem , Glicina/sangue , Glicina/farmacologia , Voluntários Saudáveis , Humanos , Masculino , Pioglitazona , Rosuvastatina Cálcica/administração & dosagem , Especificidade por Substrato , Tiazolidinedionas/administração & dosagem , Trimetoprima/administração & dosagem , Trimetoprima/farmacologia
5.
Am J Health Syst Pharm ; 74(15): 1143-1151, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28743778

RESUMO

PURPOSE: Published data on the risk of bone fractures associated with medications used for the treatment of type 2 diabetes mellitus are summarized. SUMMARY: A systematic literature search identified 108 publications on controlled trials and 6 meta-analyses addressing the potential for fractures with the use of 7 commonly used antidiabetic classes: thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, biguanides, insulin, and sulfonylureas. Among all the classes of agents evaluated, only TZDs have been clearly linked to significantly increased fracture risk (number needed to harm [NNH], 99 in one meta-analysis and 172 in another meta-analysis) and only in female patients. Interim data from an ongoing large placebo-controlled trial suggest that use of the SGLT2 inhibitor canagliflozin may be associated with an elevated rate of fractures (absolute risk increase, 1.4%; NNH, 71) and decreased total-hip bone mineral density. Published data regarding the other evaluated classes of agents generally show no effect on fracture risk; some evidence suggests a small bone-protective effect with the use of DPP-4 inhibitors. CONCLUSION: In patients with type 2 diabetes mellitus, evidence is strongest that, among antidiabetic drugs, TZDs increase the risk of bone fractures; thus, TZDs should be used with caution in women. Canagliflozin is the only SGLT2 inhibitor linked to an increased fracture rate. Metformin, sulfonylureas, insulin, DPP-4 inhibitors, and GLP-1 agonists appear to have overall neutral effects on bone fractures.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Fraturas Ósseas/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Ensaios Clínicos como Assunto/métodos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Fraturas Ósseas/sangue , Fraturas Ósseas/diagnóstico , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Metanálise como Assunto , Fatores de Risco , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/sangue , Tiazolidinedionas/uso terapêutico , Resultado do Tratamento
6.
J Med Chem ; 60(13): 5599-5612, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28609101

RESUMO

Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutaminase/antagonistas & inibidores , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/uso terapêutico , Glutaminase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ratos , Ratos Sprague-Dawley , Tiazolidinedionas/sangue , Tiazolidinedionas/uso terapêutico
7.
Eur J Pharm Sci ; 106: 431-438, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28603033

RESUMO

The purpose of this study was to evaluate in vivo supersaturation/precipitation/absorption behavior in the gastrointestinal (GI) tract based on the luminal concentration-time profiles after oral administration of pioglitazone (PG, a highly permeable lipophilic base) and its hydrochloride salt (PG-HCl) to rats. In the in vitro precipitation experiment in the classic closed system, while the supersaturation was stable in the simulated gastric condition, PG drastically precipitated in the simulated intestinal condition, particularly at a higher initial degree of supersaturation. Nonetheless, a drastic and moderate improvement in absorption was observed in vivo at a low and high dose of PG-HCl, respectively. Analysis based on the luminal concentration of PG after oral administration of PG-HCl at a low dose revealed that most of the dissolved PG emptied from the stomach was rapidly absorbed before its precipitation in the duodenum. At a high dose of PG-HCl, PG partly precipitated in the duodenum but was absorbed to some extent. Therefore, the extent of the absorption was mainly dependent on the duodenal precipitation behavior. Furthermore, a higher-than expected absorption after oral administration of PG-HCl from in vitro precipitation study may be due to the absorption process in the small intestine, which suppresses the precipitation by removal of the drug. This study successfully clarify the impact of the absorption process on the supersaturation/precipitation/absorption behavior and key absorption site for a salt formulation of a highly permeable lipophilic base based on the direct observation of in vivo luminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model and in vitro predictive dissolution tools and/or translating the in silico and in vitro data to the in vivo outcome.


Assuntos
Trato Gastrointestinal/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Precipitação Química , Trato Gastrointestinal/química , Hipoglicemiantes/sangue , Absorção Intestinal , Masculino , Pioglitazona , Ratos Wistar , Tiazolidinedionas/sangue
8.
Artigo em Inglês | MEDLINE | ID: mdl-28528664

RESUMO

A new fast LC-MS/MS method was developed for determination of alogliptin and pioglitazone in human plasma. Linearity ranges of 10-400ngmL-1 for alogliptin and 25-2000ngmL-1 for pioglitazone, were found to be suitable for their bioanalysis covering the Cmin and Cmax values of the drugs. Direct precipitation technique was used for simultaneous extraction of the drugs successfully from human plasma samples. Chromatographic separation was achieved on a BEH C18 column (50mm×2.1mm, 1.7µm) with 0.1% aqueous formic acid: acetonitrile (40:60, v/v) at a flow rate of 0.3mLmin-1. The validated method was applied to a preliminary pharmacokinetic study on human volunteers. Monitoring the transition pairs of m/z 340.18 to 116.08 for alogliptin and m/z 356.99 to 133.92 for pioglitazone, using triple quadrupole mass spectrometer with multiple reaction monitoring, was achieved in the positive mode. The validated method is accurate and suitable for further clinical applications and possible bioequivalence studies.


Assuntos
Cromatografia Líquida/métodos , Piperidinas/sangue , Piperidinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tiazolidinedionas/sangue , Tiazolidinedionas/farmacocinética , Uracila/análogos & derivados , Adulto , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Pioglitazona , Piperidinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tiazolidinedionas/química , Uracila/sangue , Uracila/química , Uracila/farmacocinética
9.
Acta Neurobiol Exp (Wars) ; 77(1): 45-56, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28379215

RESUMO

Traditionally, Morus rubra L. (Moraceae) (red mulberry) and Cornus mas L. (Cornacea) (cornelian cherry) fruits are eaten fresh and are also used in marmalades, juices, jam, natural dyes in Turkey and are believed to have beneficial effects in case of multiple health issues such as antipyretic, diarrhea and intestinal parasites. However, the effects of M. rubra and C. mas on epilepsy has not been known. This study evaluates the effects of M. rubra and C. mas extracts on penicillin-induced epileptiform activity. Sixty Wistar rats randomly divided into ten groups (n=6): control, sham, penicillin, penicillin+M. rubra extract (2.5, 5, 10, 20 mg/kg) and penicillin+C. mas extract (2.5, 5, 10 mg/kg). Epileptiform activity was induced by using penicillin (500 IU, i.c.) and electrocorticogram records (150 min) were obtained. Also, biochemical analysis in blood samples were evaluated. According to the electrocorticogram analysis, the effective dose was detected as 10 mg/kg for both C. mas and M. rubra. This dose decreased the spike frequencies of convulsions while amplitude wasn't changed by both substances. In erythrocyte studies, there were significant differences regarding nitric oxide in the control, sham and penicillin groups. There were significant differences regarding malondialdehyde in all groups. In the plasma, there were significant differences among groups regarding xanthine oxidase in the penicillin­C. mas and penicillin­M. rubra groups. There were differences regarding malondialdehyde in the penicillin-C. mas and M. rubra-C. mas groups. Both extracts reduced the frequency of epileptiform activity. After administration of the extracts malondialdehyde levels decreased also in both erythrocytes and plasma.


Assuntos
Epilepsia/tratamento farmacológico , Eritrócitos/metabolismo , Glucosídeos/química , Morus/química , Extratos Vegetais/uso terapêutico , Piranos/química , Potenciais de Ação/efeitos dos fármacos , Animais , Antibacterianos/toxicidade , Anticonvulsivantes/uso terapêutico , Ondas Encefálicas/fisiologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Epilepsia/sangue , Epilepsia/induzido quimicamente , Eritrócitos/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Óxido Nítrico/sangue , Penicilinas/toxicidade , Ratos , Ratos Wistar , Superóxido Dismutase/sangue , Tiazolidinedionas/sangue , Fatores de Tempo
10.
Biopharm Drug Dispos ; 38(6): 381-388, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28294376

RESUMO

Although the mechanism of action for peroxisome proliferator-activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. The importance of the PK profile of PPARγ agonist was evaluated for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (q.d.) or once every other day (q.2d.) as double the amount for the q.d. TREATMENT: The plasma glucose lowering effect was selected as a surrogate PD effect for an anti-diabetic effect. The model fitting was conducted using the non-linear mixed effect modeling (NONMEM) method. The indirect response model described well the plasma glucose concentration-time profile. The q.d. treatment showed a stronger impact on the plasma glucose lowering effect than did the q.2d. TREATMENT: The results of PK/PD modeling suggested that the sensitivity (i.e. EC50 ) between each group was comparable. On the other hand, the time above the effective concentration in the q.d. treatment group was longer than that in the q.2d. treatment group. The simulation of various dose regimens suggested that the much longer exposure duration within the effective level showed a stronger plasma glucose lowering effect, even with identical exposure to pioglitazone in the plasma. The PK/PD analysis clarified that the PK profile affected the pharmacological response and that continuous exposure at an appropriate effective level would be efficient for the anti-diabetic effect of the PPARγ agonist.


Assuntos
Glicemia/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/farmacocinética , Tiazolidinedionas/farmacologia , Tiazolidinedionas/farmacocinética , Animais , Hipoglicemiantes/sangue , Masculino , PPAR gama/agonistas , Pioglitazona , Ratos Wistar , Tiazolidinedionas/sangue
11.
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 de Medicamentos , 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
12.
Ann Pharm Fr ; 75(2): 105-111, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27659416

RESUMO

A liquid chromatography tandem mass spectrometry (LC-MS/MS) based method was developed for the simultaneous estimation of pioglitazone and its active metabolites in human plasma for applicability to pharmacokinetic studies. The chromatographic separation was carried on the reversed phase Peerless Basic C18, column (100×4.6mm, 5µm) at column temperature of 40°C using a binary mobile phase consisting of methanol: 5mM ammonium acetate in 0.1% formic acid (80:20, v/v). The mobile phase was run at a flow rate of 1mL/min and the sample injection was 10µL. The method utilized pioglitazone D4 (IS1) and 5-hydroxyl pioglitazone M-IV D4 (IS2) as an internal standard. The linearity of the method was validated over the range of 6.04-1503.21ng/mL for pioglitazone and 6.01-1496.28ng/mL for 5-hydroxyl pioglitazone. The mean extraction recovery of PIO & HPIO from the spiked plasma was found to be 94.92% for pioglitazone and 96.13% for 5-hydroxy pioglitazone. The developed method can be successfully employed in healthy human volunteers to monitor the pharmacokinetics profile of pioglitazone.


Assuntos
Hipoglicemiantes/sangue , Tiazolidinedionas/sangue , Cromatografia Líquida de Alta Pressão , Humanos , Pioglitazona , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
13.
Drug Metab Pers Ther ; 31(3): 165-71, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27522101

RESUMO

BACKGROUND: Severe forms of non-alcoholic fatty liver disease (NAFLD) adversely affect the liver physiology and hence the pharmacokinetics of drugs. Here, we investigated the effect of NAFLD on the pharmacokinetics of rosiglitazone, an insulin sensitizer used in the treatment of type 2 diabetes. METHODS: Male C57BL/6 mice were divided into two groups. The first group (n=14) was fed with normal chow feed and the second group (n=14) was fed with 60% high-fat diet (HFD) and 40% high fructose liquid (HFL) for 60 days to induce NAFLD. The development of NAFLD was confirmed by histopathology, liver triglyceride levels and biochemical estimations, and used for pharmacokinetic investigations. Rosiglitazone was administered orally at 30 mg/kg dose. At predetermined time points, blood was collected and rosiglitazone concentrations were determined using LC/MS/MS. Plasma concentrations were subjected to non-compartmental analysis using Phoenix WinNonlin (6.3), and the area under the plasma concentration-time curve (AUC) was calculated by the linear-up log-down method. RESULTS: HFD and HFL diet successfully induced NAFLD in mice. Rosiglitazone pharmacokinetics in NAFLD animals were altered significantly as compared to healthy mice. Rosiglitazone exposure increased significantly in NAFLD mice (2.5-fold higher AUC than healthy mice). The rosiglitazone oral clearance was significantly lower and the mean plasma half-life was significantly longer in NAFLD mice as compared to healthy mice. CONCLUSIONS: The NAFLD mouse model showed profound effects on rosiglitazone pharmacokinetics. The magnitude of change in rosiglitazone pharmacokinetics is similar to that observed in humans with moderate to severe liver disease. The present animal model can be utilized to study the NAFLD-induced changes in the pharmacokinetics of different drugs.


Assuntos
Hepatopatia Gordurosa não Alcoólica/metabolismo , Tiazolidinedionas/farmacocinética , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Xarope de Milho Rico em Frutose/efeitos adversos , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Rosiglitazona , Tiazolidinedionas/sangue
14.
J Pharm Biomed Anal ; 129: 21-27, 2016 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-27392173

RESUMO

Patients with pulmonary arterial hypertension (PAH) are currently treated with more than one drug. Sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and rosiglitazone, a peroxisome proliferator-activated receptor γ (PPAR-γ) activator, is one of those combinations that could be used in PAH. To monitor the pharmacokinetics of sildenafil in the presence of rosiglitazone, we have developed and validated a sensitive, specific and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. We have used this validated method to study the pharmacokinetics of sildenafil and rosiglitazone after intravenous administration of sildenafil alone or a combination of sildenafil plus rosiglitazone to adult male Sprague-Dawley rats. Sildenafil and rosiglitazone were extracted from plasma by protein precipitation with methanol. With an octadeuterated sildenafil as the internal standard, the drugs were separated via gradient elution using a C18 column and formic acid in methanol or in water as the mobile phase with a flow rate of 0.25mL/min. Both sildenafil and rosiglitazone samples in rat plasma produced linear response, when the concentration ranged between 5 and 1000ng/mL (r(2)>0.99). The pharmacokinetics study suggests that intravenous co-administration rosiglitazone plus sildenafil increases the plasma concentration of sildenafil and extends the drug's elimination half-life.


Assuntos
Cromatografia Líquida/normas , Citrato de Sildenafila/sangue , Espectrometria de Massas em Tandem/normas , Tiazolidinedionas/sangue , Administração Intravenosa , Animais , Cromatografia Líquida/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Rosiglitazona , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/análise , Espectrometria de Massas em Tandem/métodos , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/análise
15.
Drug Metab Dispos ; 44(8): 1364-71, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27260150

RESUMO

The glucose-lowering drug pioglitazone undergoes hepatic CYP2C8-mediated biotransformation to its main metabolites. The antiplatelet drug clopidogrel is metabolized to clopidogrel acyl-ß-d-glucuronide, which was recently found to be a strong time-dependent inhibitor of CYP2C8 in humans. Therefore, we studied the effect of clopidogrel on the pharmacokinetics of pioglitazone. In a randomized crossover study, 10 healthy volunteers ingested either 300 mg of clopidogrel on day 1, and 75 mg on days 2 and 3, or placebo. Pioglitazone 15 mg was administered 1 hour after placebo and clopidogrel on day 1. Plasma concentrations of pioglitazone, clopidogrel, and their main metabolites were measured up to 72 hours. Clopidogrel increased the area under the plasma concentration-time curve (AUC0-∞) of pioglitazone 2.1-fold [P < 0.001, 90% confidence interval (CI) 1.8-2.6] and prolonged its half-life from 6.7 to 11 hours (P = 0.002). The peak concentration of pioglitazone was unaffected but the concentration at 24 hours was increased 4.5-fold (range 1.6-9.8; P < 0.001, 90% CI 3.17-6.45) by clopidogrel. The M-IV-to-pioglitazone AUC0-∞ ratio was 49% (P < 0.001, 90% CI 0.40-0.59) of that during the control phase, indicating that clopidogrel inhibited the CYP2C8-mediated biotransformation of pioglitazone. Clopidogrel increases the exposure to pioglitazone by inhibiting its CYP2C8-mediated biotransformation. In consequence, use of clopidogrel may increase the risk of fluid retention and other concentration-related adverse effects of pioglitazone.


Assuntos
Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Citocromo P-450 CYP2C8/metabolismo , Hipoglicemiantes/sangue , Inibidores da Agregação de Plaquetas/administração & dosagem , Tiazolidinedionas/sangue , Ticlopidina/análogos & derivados , Administração Oral , Adulto , Área Sob a Curva , Biotransformação , Clopidogrel , Estudos Cross-Over , Citocromo P-450 CYP2C8/genética , Inibidores do Citocromo P-450 CYP2C8/efeitos adversos , Esquema de Medicação , Interações de Medicamentos , Feminino , Finlândia , Genótipo , Meia-Vida , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Masculino , Taxa de Depuração Metabólica , Variantes Farmacogenômicos , Fenótipo , Pioglitazona , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/sangue , Inibidores da Agregação de Plaquetas/farmacocinética , Medição de Risco , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/farmacocinética , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/sangue , Ticlopidina/farmacocinética , Adulto Jovem
16.
Reprod Toxicol ; 61: 162-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27067916

RESUMO

Despite the fact that fetal drug exposure is common, the disposition of drugs in the fetus is poorly understood. This study aimed to investigate fetal placental and non-placental disposition of rosiglitazone in the pregnant ewe. Steady state was reached after day 5 of fetal infusion, and were ∼1.8 fold higher than maternal concentrations (P<0.001). The AUC for fetal rosiglitazone concentration throughout the infusion was inversely correlated with placental and fetal weight. Metabolic activity of the fetal liver microsomes were ∼25 fold lower than maternal microsomes (P<0.001). The findings suggest that trans-placental transfer is the major route through which rosiglitazone is cleared from the fetal compartment, while non-placental hepatic elimination makes only a minor contribution. This supports a limited capacity of the fetus for eliminating this class of drugs, and highlights the potential for drug toxicity when administering pharmacotherapy to the mother/fetus in human pregnancy.


Assuntos
Feto/metabolismo , Hipoglicemiantes/farmacocinética , Troca Materno-Fetal , Tiazolidinedionas/farmacocinética , Líquido Amniótico/metabolismo , Animais , Feminino , Hipoglicemiantes/sangue , Microssomos Hepáticos/metabolismo , Placenta/metabolismo , Gravidez , Rosiglitazona , Ovinos , Tiazolidinedionas/sangue
17.
Neurol Res ; 38(4): 294-300, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27098232

RESUMO

OBJECTIVES: Potassium channels participate in cellular and molecular signalling pathways regulating the life and death of neurons. In this study, effect of pretreatment with potassium channel blockers of 4-aminopyridine (4-AP) and tetraethylammonium (TEA) on the behavioural symptoms of 6-hydroxydopamine (6-OHDA)-induced Parkinsonism was evaluated. METHODS: 6-OHDA was injected into right striatum of adult male Wistar rats using stereotaxic surgery. Severity of 6-OHDA-induced Parkinsonism was assessed by conventional behavioural tests. 4-AP and TEA were injected twice per day intraperitoneally, before 6-OHDA injection to 15 days after that. Also, malondialdehyde (MDA) concentration as a marker of oxidative stress was measured in rat sera. RESULTS: Pretreatment with 4-AP (0.5 and 1 mg/kg) and TEA (2 and 5 mg/kg) attenuated significantly behavioural symptoms of 6-OHDA-induced Parkinsonism. Application of both 4-AP and TEA together was more effective than the effect of each one of these blockers alone. 6-OHDA increased MDA concentration but pretreatment with 4-AP prevented of 6-OHDA-induced increase in MDA. On the other hand, pretreatment with TEA and combination of TEA and 4-AP could not prevent of 6-OHDA-induced oxidative stress. DISCUSSION: Since severity of behavioural symptoms of 6-OHDA-induced Parkinsonism is correlated to the degree of nigral dopaminergic cell death, we suggest that antiparkinsonism effect of TEA and 4-AP was mediated by their neuroprotective effect. Because, both Parkinsonism in rat and PD in human, the main pathophysiological hallmark, is neurodegeneration of dopaminergic neurons in substantia nigra, we suggest doing clinical trials for evaluation of effectiveness of 4-AP and TEA in slowing down of PD progress.


Assuntos
4-Aminopiridina/uso terapêutico , Transtornos Mentais/etiologia , Transtornos Mentais/prevenção & controle , Transtornos Parkinsonianos/complicações , Bloqueadores dos Canais de Potássio/uso terapêutico , Tetraetilamônio/uso terapêutico , Adrenérgicos , Animais , Apomorfina/farmacologia , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Lateralidade Funcional/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/sangue , Transtornos Parkinsonianos/induzido quimicamente , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Wistar , Tiazolidinedionas/sangue
18.
Drug Deliv ; 23(2): 601-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-24937378

RESUMO

Pioglitazone (PZ) an anti-hyperglycemic agent is used in the treatment of type 2 diabetes. The aim of this study was to design PZ-loaded nanostructured lipid carriers (NLC) to investigate the bioavailability improvement by transdermal delivery. PZ NLCs were prepared using high-pressure homogenization followed by ultrasonication. The NLCs were evaluated for particle size analysis, drug loading, ex vivo skin transport studies and in vivo bioactivity study. The prepared NLCs had a mean size of 166.05 nm and drug loading of 10.41% with flux value of 47.36 µg/cm(2)/h. The entrapment of PZ is >70% in the NLCs with enhancement ratio of 3.2 times. The in vivo pharmacokinetic study showed 2.17 times enhancement in bioavailability study and pharmacodynamics study showed that PZ NLC-based transdermal therapeutic system (PNLG-TTS) lowers blood sugar level in a sustained pattern for a prolonged period of time as compared to Piosys tablet (marketed). The shelf life of the optimized formulation was found to be 1.83 years. These results clearly provide a lead that above NLCs-based TTS is potential controlled release formulation for PZ and could be a promising drug delivery system for the treatment of diabetes.


Assuntos
Glicemia/efeitos dos fármacos , Portadores de Fármacos , Hipoglicemiantes/administração & dosagem , Lipídeos/química , Nanopartículas , Absorção Cutânea , Pele/metabolismo , Tiazolidinedionas/administração & dosagem , Administração Cutânea , Animais , Disponibilidade Biológica , Biomarcadores/metabolismo , Glicemia/metabolismo , Cristalografia por Raios X , Composição de Medicamentos , Estabilidade de Medicamentos , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Nanotecnologia , Tamanho da Partícula , Pioglitazona , Difração de Pó , Pressão , Ratos Wistar , Sonicação , Tecnologia Farmacêutica/métodos , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética , Ultrassom
19.
Biopharm Drug Dispos ; 36(9): 603-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26296069

RESUMO

PURPOSE: Repaglinide and pioglitazone are both CYP2C8 and CYP3A4 substrates. This study was to determine whether repaglinide has an inhibitory effect on the metabolism of pioglitazone in vitro, in silico and in vivo. METHOD: In vitro, the effect of repaglinide on the metabolism of pioglitazone was assessed in pooled human liver microsomes. In silico, an IVIVE-PBPK linked model was built with Simcyp®. Then, a randomized, 2-phase cross-over clinical study was conducted in 12 healthy volunteers. RESULTS: Repaglinide showed a strong inhibitory effect on the metabolism of pioglitazone in vitro (Ki = 0.0757 µm), [I]/Ki > 0.1. The Simcyp® prediction ratios of AUC and Cmax between the two treatment groups were both about 1.01. The pharmacokinetics of pioglitazone in clinical trials showed no significant difference between these two treatment groups (p > 0.05). CONCLUSION: Repaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo, which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and to the high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro.


Assuntos
Carbamatos/farmacocinética , Hipoglicemiantes/farmacocinética , Microssomos Hepáticos/efeitos dos fármacos , Modelos Biológicos , Piperidinas/farmacocinética , Tiazolidinedionas/farmacocinética , Adolescente , Adulto , Algoritmos , Biotransformação/efeitos dos fármacos , Carbamatos/sangue , Carbamatos/química , Carbamatos/metabolismo , Fenômenos Químicos , Biologia Computacional , Estudos Cross-Over , Interações de Medicamentos , Sistemas Especialistas , Meia-Vida , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Taxa de Depuração Metabólica , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Pioglitazona , Piperidinas/sangue , Piperidinas/química , Piperidinas/metabolismo , Software , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Tiazolidinedionas/metabolismo , Adulto Jovem
20.
J Pharm Biomed Anal ; 115: 375-82, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26275726

RESUMO

The objective of this study was to elucidate the chemical structure of the metabolites derived from lobeglitazone (LB) during its incubation with rat liver microsomes and to characterize the kinetics of formation of the major metabolite M1 in vivo. Using high performance liquid chromatography coupled with a hybrid quadrupole linear ion trap, the metabolites were derived from LB during its incubation with rat liver microsomes. From various fragmentation patterns obtained from the metabolites, LB was biotransformed into 5 metabolites in the incubation, in which demethylation and hydroxylation appeared to be the principle metabolic pathways in vitro; Amongst the five primary metabolites, M1, a demethylated derivative of LB, appeared to be the major metabolite of LB, based on a comparison on the peak intensities in the ion chromatogram. In a study of the in vivo kinetics of formation of M1 in rats, the rate of formation of M1 from LB was determined to be 0.252 and 0.216mL/min/kg at doses of 0.5mg/kg and 2mg/kg of LB, respectively, suggesting that the kinetics of M1 formation were linear in the dose range tested. Considering the fact that LB is primarily eliminated by hepatic metabolism in rats, the formation of M1 accounts for approximately 7.50-9.76% of the overall elimination of LB in rats.


Assuntos
Hipoglicemiantes/farmacocinética , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Pirimidinas/farmacocinética , Tiazolidinedionas/farmacocinética , Administração Intravenosa , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Remoção de Radical Alquila , Eliminação Hepatobiliar , Hidroxilação , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Masculino , Modelos Biológicos , Estrutura Molecular , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirimidinas/química , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/sangue , Tiazolidinedionas/química
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