RESUMO
1. The present work investigated the pharmacokinetic and tissue distribution as well as acute toxicity of a new chemical entity (NCE), the anticancer candidate LaSOM 65 in Wistar rats. 2. LaSOM 65 pharmacokinetics was investigated after intravenous (i.v., 1 mg/kg) and oral (p.o., 10 and 30 mg/kg) dosing. Tissue distribution was assessed after i.v. bolus dose. Acute toxicity was evaluated after i.v. (1, 2.5 and 5 mg/kg) and p.o. (50, 100 and 150 mg/kg) administration. 3. Short half-life (1.75 ± 0.71 h), a clearance of 0.85 ± 0.18 L/h/kg and a volume of distribution of 1.76 ± 0.24 L/kg were observed after i.v. dosing. The compound showed good bioavailability and linear pharmacokinetics after oral doses. The NCE distributes consistently in lung and fatty tissues, with penetration ratios of 2.7 and 1.4, respectively. The other tissues investigated presented smaller penetration ratios. Adverse clinical symptoms were observed only after i.v. administration, and regressed 3 h after dosing. Compared with controls, no statistical differences were found for serum analysis, body weight and relative organ weight, indicating no acute toxicological effects. 4. Overall, LaSOM 65 showed good pharmacokinetic characteristics and no signs of acute toxicity, indicating that it is a promising anticancer candidate.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Tionas/farmacocinética , Tionas/toxicidade , Tecido Adiposo/metabolismo , Administração Intravenosa , Administração Oral , Análise de Variância , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Disponibilidade Biológica , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Pulmão/metabolismo , Masculino , Estrutura Molecular , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Wistar , Tionas/administração & dosagem , Tionas/química , Distribuição Tecidual , Testes de Toxicidade AgudaRESUMO
This work aimed to investigate plasma pharmacokinetics and tissue distribution of a new acridine derivative 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) and its 1-oxo-AC04 metabolite disposition in Wistar rats. After a single AC04 1.5 mg/kg intravenous (i.v.) bolus dose, blood samples were taken up to 120 h. Plasma samples were deproteinization, and AC04 and metabolite were quantified by validated liquid chromatography in tandem with mass spectrometry method. Protein binding was determined by ultrafiltration. AC04 tissue disposition was evaluated after i.v. bolus dose. Individual AC04 concentration-time profiles were best fitted by a two-compartment model showing CL(tot) of 3.4 ± 3.4 L/h/kg, Vd(SS) of 137.9 ± 91.4 L/kg, AUC(0-∞) of 788 ± 483 ng·h/mL and a t(1/2) of 45.5 ± 31.5 h. Protein binding was 98.1 ± 1.6%. AC04 showed higher penetration into the lung, spleen and liver, with AUC(0-96) of 798,443, 263,211 and 303,722 ng·h/mL, respectively. The 1-oxo-AC04 metabolite represented 10% of AC04 plasma concentration, showing a t(1/2) of 23.2 ± 10.4 h. These results suggest that, despite the small free plasma fraction, AC04 penetrates extensively reaching high concentrations in most tissues residing for a long time, which is important for its activity on solid tumours. All results combined indicate that AC04 is potentially a good antitumour candidate.
Assuntos
Acridinas/farmacocinética , Antineoplásicos/farmacocinética , Tiazolidinedionas/farmacocinética , Acridinas/uso terapêutico , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Masculino , Neoplasias/tratamento farmacológico , Ratos , Tiazolidinedionas/sangue , Tiazolidinedionas/uso terapêutico , Distribuição TecidualRESUMO
The study aimed to investigate the pharmacokinetics and tissue distribution of the benzaldehyde semicarbazone (BS) a potential antiepileptic drug, administered as a free drug or complexed beta-cyclodextrin (BS/beta-CD). Free BS and BS/beta-CD were administered to male Wistar rats as a 10mg/kg intravenous bolus dose. For the oral route, 50mg/kg and 100mg/kg doses of the free drug and 50mg/kg of the complex were administrated and plasma concentrations were determinated by a validated HPLC-UV method. Individual profiles were evaluated by non-compartmental and compartmental analysis using Excel and Scientist, respectively. Free BS plasma protein binding was 34+/-5%. A one-compartmental model adequately described all the plasma profiles for both formulations. After intravenous (10mg/kg) and oral (50mg/kg) administration, the V(d) (1.6+/-0.5 and 2.2+/-0.8L/kg, respectively) and the Cl(tot) (1.4+/-0.5 and 1.8+/-0.5L/hkg, respectively) determinated for the BS/beta-CD complex were higher than those obtained for the free drug, but the t(1/2) (0.8+/-0.1h) was similar (p<0.05). The oral bioavailability of the BS/beta-CD complex (approximately 37%) was approximately 2-fold of the free BS ( approximately 20%). The higher drug brain penetration (2.8) after BS/beta-CD dosing and the longer mean residence time in this organ, regardless of the administration route, reveals that the complex may be a potential drug carrier for the central nervous system delivery of BS.
Assuntos
Anticonvulsivantes/farmacocinética , Semicarbazonas/farmacocinética , beta-Ciclodextrinas/química , Animais , Anticonvulsivantes/administração & dosagem , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Masculino , Ratos , Ratos Wistar , Semicarbazonas/administração & dosagem , Espectrofotometria UltravioletaRESUMO
OBJECTIVES: Novel 5-benzilidene thiazolidinones have been synthesized and exhibited anti-inflammatory activity. In this work one of the compounds of the thiazolidinone chemical series, (5Z,E)-3-[2-(4-chlorophenyl)-2-oxoethyl]-5-(1H-indol-3-ylmethylene)-thiazolidine-2,4-dione (PG15) was investigated aiming to determine the drug's anti-inflammatory potential in pre-clinical studies. METHODS: Methods used included the in-vitro inhibition of cyclooxygenase-1 and -2, in-vivo evaluation of anti-inflammatory activity by air pouch and peritonitis models and the pharmacokinetic profile after intravenous (3 mg/kg) and oral (3 and 6 mg/kg) dosing to rats. KEY FINDINGS: A two-compartment model with a fast distribution and an elimination half-life of 5.9 +/- 3.8 h described the PG15 plasma profile after intravenous dosing. PG15 showed an erratic and rapid absorption following oral administration with peak concentrations between 0.5 and 1 h. PG15 0.1 microM inhibited more than 30% and 13% of purified cyclooxygenase-1 and -2 activity in vitro, respectively. A lack of dose dependency was observed for the anti-inflammatory effect in the dose range investigated (0.8-50 mg/kg), with a maximum of 67.2 +/- 4.6% inhibition of leucocyte migration in the carrageenan-induced air pouch model obtained with the 3 mg/kg dose, similar to that observed for indometacin 10 mg/kg. CONCLUSIONS: The erratic absorption of PG15 observed after oral dosing could explain the lack of anti-inflammatory dose dependency.