RESUMO
Tuberculosis chemotherapy involves combination of the drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) for a 6-month period. The present work investigated the influence of RMP and PYR on the pharmacokinetic parameters of INH when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg+RMP 100 mg; INH 100 mg+PYR 350 mg; INH 100 mg+PYR 350 mg+RMP 100 mg. It was found that the co-administration of PYR caused an increase in the INH distribution volume (V(d)/F), half-life of elimination (t(1/2beta)) and clearance (Cl(T)/F), and a decrease in the area under curve 0 to 24 h (AUC). Co-administration of RMP caused an increase in the Cl(T)/F and a decrease in the AUC. The combination INH+PYR+RMP caused an increase in the Cl(T)/F and a decrease in the AUC. These significant pharmacokinetic interactions between the tuberculostatic drugs might be related to differences in the therapeutic and toxic effects.
Assuntos
Antibióticos Antituberculose/farmacologia , Antituberculosos/farmacologia , Antituberculosos/farmacocinética , Isoniazida/farmacocinética , Pirazinamida/farmacologia , Rifampina/farmacologia , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Meia-Vida , Masculino , Ratos , Ratos WistarRESUMO
Hepatotoxicity is the main concern during tuberculosis chemotherapy with the first-line drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR). Since these hepatotoxic events have been associated with INH metabolites, the study aimed to measure the area under curve (AUC) parameter for INH and its metabolites acetylisoniazid (AcINH), hydrazine (Hz) and acetylhydrazine (AcHz), when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg + RMP 100 mg; INH 100 mg + PYR 350 mg; INH 100 mg + PYR 350 mg + RMP 100 mg. It was found that co-administration of RMP, PYR and RMP + PYR caused a significant decrease in the AUC for INH. Co-administration of PYR was the only treatment that caused a significant increase in the AUC for Hz and a decrease in the AUC for its acetylated product AcHz. The AUC for AcINH was not significantly altered in any experimental group. In conclusion, the increased metabolism of INH in all the drug combinations and the significantly higher production of Hz in the group INH + PYR might be linked with exacerbated hepatotoxic effects of these drug associations.
Assuntos
Isoniazida/farmacocinética , Pirazinamida/farmacocinética , Rifampina/farmacocinética , Animais , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/metabolismo , Antibióticos Antituberculose/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Hidrazinas/análise , Hidrazinas/metabolismo , Intubação Gastrointestinal , Isoniazida/administração & dosagem , Isoniazida/metabolismo , Masculino , Pirazinamida/administração & dosagem , Pirazinamida/metabolismo , Ratos , Ratos Wistar , Rifampina/administração & dosagem , Rifampina/metabolismo , Fatores de TempoRESUMO
There is a growing body of evidence that melatonin and its oxidation product, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), have anti-inflammatory properties. From a nutritional point of view, the discovery of melatonin in plant tissues emphasizes the importance of its relationship with plant peroxidases. Here we found that the pH of the reaction mixture has a profound influence in the reaction rate and products distribution when melatonin is oxidized by the plant enzyme horseradish peroxidase. At pH 5.5, 1 mm of melatonin was almost completely oxidized within 2 min, whereas only about 3% was consumed at pH 7.4. However, the relative yield of AFMK was higher in physiological pH. Radical-mediated oxidation products, including 2-hydroxymelatonin, a dimer of 2-hydroxymelatonin and O-demethylated dimer of melatonin account for the fast consumption of melatonin at pH 5.5. The higher production of AFMK at pH 7.4 was explained by the involvement of compound III of peroxidases as evidenced by spectral studies. On the other hand, the fast oxidative degradation at pH 5.5 was explained by the classic peroxidase cycle.