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1.
J Pharm Biomed Anal ; 179: 113000, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31787460

RESUMO

Thiazolidinediones are known for their activity against Type 2 diabetes and are currently being repurposed for their potent anti-cancer activity. In the present study, we have assessed in vitro metabolic properties and in vivo pharmacokinetic parameters of a novel thiazolidinedione derivative, BIT-15-67, a potential anticancer compound. BIT-15-67 showed low solubility in aqueous buffers at different pH values. The permeability was determined across the Caco-2 monolayer and BIT-15-67 showed high permeability and an efflux ratio of less than 2 suggesting that it is not a substrate of the efflux transporters (P-gp & BCRP). The plasma protein binding was evaluated by equilibrium dialysis and the compound exhibited moderate binding to mouse and rat plasma proteins. BIT-15-67 was stable (half-life > 30 min.) in mouse, rat, dog and human liver microsomes and unstable (half-life <15 min.) in rat hepatocytes suggesting possible Phase II metabolism. Liquid chromatography-tandem mass spectrometry was used to identify Phase I and Phase II metabolites. One of each Phase I and Phase II metabolites have been identified in rat hepatocytes samples. The BIT-15-67 is not an inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The PK parameters were determined in both male and female Wistar rats after single intravenous dose administration of BIT-15-67. In rats, the mean plasma clearance of BIT-15-67 was higher in males than in females and the terminal plasma elimination half-life was shorter in males than in females. The compound was highly distributed in the tissues. Overall, the absolute oral bioavailability was 5-fold higher in females (38 %) than in males (7 %). In female nude mice with tumors, BIT-15-67 was well distributed among the collected tissues with the highest concentration in the liver. The ratio of the concentrations in tumor vs. the plasma was 0.5 which could be an important attribute in the development of the compound for anti-cancer research.

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
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