Targeting JNK as a Novel Approach to Drug Metabolism Regulation

Abstract

The management of pharmacokinetics and pharmacodynamics of drugs constitutes an approach for personalizing pharmacotherapy. This can be achieved by controlling xenobiotic metabolism. This research aimed to study the possibility of controlling the biotransformation of substances in the body through targeted regulation of intracellular signal transduction. By UPLC-MS/MS, the effect of JNK inhibitors on the metabolism of venlafaxine xenobiotic by liver cells was investigated in vitro. The blocking of JNK in hepatic homogenate cells containing the antidepressant was accompanied by an increase in the intensity of its biotransformation. There was a significant increase in forming a single pharmacologically active metabolite of O-desmethylvenlafaxine in the cell suspension and its further chemical conversion. Data from experiments indicate marked induction of venlafaxine metabolism by the JNK inhibitor. These properties of JNK inhibitors can be used to develop a novel approach to the characterization of antidepressant treatment. Also, the results indicate the prospect of studying activity modifiers of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop methods of controlling the process of xenobiotic transformation and create a novel class of pharmaceuticals - targeted drug metabolism regulators.