RESUMO
A procedure for the determination of oseltamivir in human plasma by high-performance liquid chromatography( tandem mass spectrometry (HPLC-MS/MS) was proposed and validated. Arapid and easy-to-use method of liquid(liquid extraction with ethyl acetate using venlafaxine as an internal standard was used during sample preparation. The addition of benzoic acid to aqueous acetonitrile solutions of the analyte was shown to prevent its oxidative degradation. The detection limit and limit of quantitation were 0.08 and 0.30 ng/mL, respectively; the calibration range, 0.3-200 ng/mL (R 2 = 0.9937); the total analysis time, 3.2 min. The within- and between-run accuracy ranged from 97 to 105%. The precision was <10%. The proposed procedure was characterized by selective determination of the analyte, the absence of significant matrix effects, the ability to dilute samples with high analyte concentrations, and satisfactory extraction recovery (≥89%). The analyte was stable when stored in plasma samples (4 h at room temperature, 31 d at (80°C, after three freeze(thaw cycles) and extracts under autosampler storage conditions (24 h at 15°C). The procedure was successfully used for oseltamivir quantitation in actual plasma samples from healthy volunteers obtained during a bioequivalence study of the new generic drug.
RESUMO
We studied the role of JNK in the regulation of the metabolism of xenobiotic venlafaxine by liver cells under in vitro conditions. The inhibitory role of this protein kinase in the biotransformation of this psychotropic agent by hepatocytes was demonstrated. JNK inhibitor added to the liver homogenate containing antidepressant enhanced and accelerated the formation of the only pharmacologically active venlafaxine metabolite O-desmethylvenlafaxine in the cell suspension. The results show the promise of studying modifiers of activity of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop a fundamentally new approach to control the transformation of xenobiotics and to create a new class of pharmaceutical, target regulators of drugs metabolism.
Assuntos
Hepatócitos/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Xenobióticos/metabolismo , Animais , Biotransformação/efeitos dos fármacos , Succinato de Desvenlafaxina/metabolismo , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Oximas/farmacologia , Quinoxalinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Cloridrato de Venlafaxina/metabolismoRESUMO
Experiments of outbred rats with modeled xenobiotic load with acetylsalicylic acid (250 mg/kg for 7 days) revealed inhibition of mitochondrial respiration rate in states of rest and active phosphorylation, inhibition of succinate-dependent oxidation pathway, and a decrease in energization of organelles in the heart. For correction of the observed changes in energy production, succinic acid was preventively administered in a dose of 50 mg/kg for 7 days, which abolished the negative metabolic shifts in myocardial mitochondria. Comparison of pharmacokinetics of acetylsalicylic acid and acetylsalicylic acid against the background of succinate treatment performed on rabbits revealed complete coincidence of the studied parameters, which attests to the possibility of prevention of mitochondrial dysregulations with this Krebs cycle intermediate.