ABSTRACT
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.
Subject(s)
Hepatocytes/metabolism , JNK Mitogen-Activated Protein Kinases/physiology , Xenobiotics/metabolism , Animals , Biotransformation/drug effects , Desvenlafaxine Succinate/metabolism , Dose-Response Relationship, Drug , Hepatocytes/drug effects , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Liver/drug effects , Liver/metabolism , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred C57BL , Oximes/pharmacology , Quinoxalines/pharmacology , Signal Transduction/drug effects , Signal Transduction/physiology , Venlafaxine Hydrochloride/metabolismABSTRACT
We studied pharmacokinetics of a new analgesic based on a hexaazaisowurtzitane derivative (thiowurtzine, TWZ). A method for measuring TWZ in organs and tissues by HPLC/MS/MS was developed and validated. The sensitivity of the method under conditions of intragastric administration of TWZ to rats in a dose of 100 mg/kg is 0.5 ng/ml (calibration curve 0.5-400 ng/ml). The concentrations of the substance (Cmax) in the plasma, organs, and tissues of animals were 20-100 ng/ml, the time to reach the maximum concentration after a single dose (Tmax) was 2 h. The mean retention time of the substance in the body ranged from 5.67 to 17.15 h after administration. The highest concentrations were found in excretory organs (liver and kidneys), the substance also actively penetrated into muscle tissue. The medium concentrations were found in the brain and adipose tissue. The tropism to the heart tissues was minimal.
