Experimental therapy of Nonalcoholic steatohepatitis, and Intrahepatic cholestasis of Pregnancy
The aim of this branch of research is to study liver effects (pharmacodymacs) of current or potential drugs in common liver disorders. Attention is focused on nonalcoholic steatohepatitis (NASH) as a common disease accompanying numerous metabolic and cardiovascular disorders, and intrahepatic cholestasis (ICP), the most frequent liver disorder during pregnancy. We combine appropriate in vivo
models of these situations with detailed analysis of involved regulatory and executive molecules in order to identify dose-response relationship, and responsible mechanisms. Equally important is also description of effects of all such agents in healthy animals because these drugs are frequently used also in clinical situations without NASH and ICP.
Modulation of bile acid homeostasis, and bile production.
Bile production is an essential function of the liver and serves as an irreplaceable excretory pathway for elimination of lipophilic endo- and xenobiotics such as cholesterol, BA, bilirubin or drugs. Moreover, as major components of bile, BA are required for micelle formation, intestinal fat digestion, regulation of bacterial growth, and immune response and production of regulatory mediators released to portal circulation such as fibroblast growth factor 19 or glucagon-like peptide 1. In addition, BA as the major metabolites of cholesterol, act as hormones by agonism at several receptors such as farnesoid X receptor (FXR), the G protein-coupled bile acid receptor 1 (TGR5), sphingosine-1-phosphate receptor 2, or pregnane X receptor (PXR), and regulate numerous liver functions including glucose and triglyceride metabolism. Stimulation of these receptors demonstrates promising positive effects in liver diseases such as nonalcoholic steatohepatitis (NASH) or intrahepatic cholestasis. On the other hand, BA accumulated during different forms of cholestasis may have a direct toxic effect on liver cells and tissues. Regulation of bile production and BA homeostasis are therefore key events in liver physiology and pathophysiology. Numerous regulatory events exist in whole process, especially nuclear receptors FXR, PXR, CAR, VDR, as well as feedback and inflammatory signaling triggering mitogen-activated kinases, or directly interacting with promotor sequences as we have recently detected for iron-mediated changes. The aim of this branch of research is therefore the identification of regulatory mechanisms of BA homeostasis and bile production, and characterization of possible pharmacological modulation.
This part is solved in cooperation with the group of prof. PharmDr. Petr Pavek, Ph.D.
and prof. PharmD. Petr Nachtigal, Ph.D.
from Faculty of Pharmacy in Hradec Kralove.
Drug pharmacokinetics in preclinical studies
Knowledge of pharmacokinetic characteristics of evaluated drugs, i.e. absorption, distribution, metabolism, and excretion is an essential prerequisite for successful pharmacotherapy with minimum of adverse reactions and drug-drug interactions. We therefore focus on evaluation of kinetic parameters including clearance, biliary and urinary secretion, volume of distribution, biological half-life and bioavailability in current or developing drugs. Essential approach is the usage of suitable in vivo
and in vitro
models together with advanced analytical and mathematical methods.