Search

Start Over Creator Anzenbacher, Pavel

2. In vitro and in silico studies of interaction of synthetic 2,6,9-trisubstituted purine kinase inhibitors BPA-302, BP-21 and BP-117 with liver drug-metabolizing cytochromes P450

Creator:
Špičáková, Alena, Kraus, Petr, Gucký, Tomáš, Kryštof, Vladimír, Strnad, Miroslav, Bazgier, Václav, Otyepka, Michal, Kubíčková, Vendula, Poruba, Martin, Rácová, Zuzana, Zapletalová, Iveta, and Anzenbacher, Pavel
Format:
počítač and online zdroj
Type:
model:article and TEXT
Subject:
cytochrome P450 inhibition, high performance liquid chromatography, cyclin-dependent kinase inhibitor, FLT3-ITD inhibitor, and drug metabolism
Language:
English
Description:
An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA-302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 µmol·l-1 ). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.
Rights:
http://creativecommons.org/publicdomain/mark/1.0/ and policy:public

4. Presence or absence of microbiome modulates the response of mice organism to administered drug nabumetone

Creator:
Jourová, Lenka, Lišková, Barbora, Lněničková, Kateřina, Zemanová, Nina, Anzenbacher, Pavel, Hermanová, Petra, Hudcovic, Tomáš, Kozáková, Hana, and Anzenbacherová, Eva
Format:
počítač and online zdroj
Type:
model:article and TEXT
Subject:
gut microbiome, cytochromes P450, germ-free mice, nabumetone, and metabolism of drugs
Language:
English
Description:
The gut microbiota provides a wide range of beneficial functions for the host, and has an immense effect on the host’s health status. The presence of microbiome in the gut may often influence the effect of an orally administered drug. Molecular mechanisms of this process are however mostly unclear. We investigated how the effect of a nonsteroidal drug nabumetone on expression of drug metabolizing enzymes (DMEs) in mice intestine and liver is changed by the presence of microbiota, here, using the germ free (GF) and specific pathogen free (SPF) BALB/c mice. First, we have found in a preliminary experiment that in the GF mice there is a tendency to increase bioavailability of the active form of nabumetone, which we have found now to be possibly influenced by differences in expression of DMEs in the GF and SPF mice. Indeed, we have observed that the expression of the most of selected cytochromes P450 (CYPs) was significantly changed in the small intestine of GF mice compared to the SPF ones. Moreover, orally administered nabumetone itself altered the expression of some CYPs and above all, in different ways in the GF and SPF mice. In the GF mice, the expression of the DMEs (CYP1A) responsible for the formation of active form of the drug are significantly increased in the small intestine and liver after nabumetone application. These results highlight the importance of gut microbiome in processes involved in drug metabolism in the both gastrointestinal tract and in the liver with possible clinical relevance.
Rights:
http://creativecommons.org/publicdomain/mark/1.0/ and policy:public