Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F18%3A10383151" target="_blank" >RIV/00216208:11160/18:10383151 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0006295218301564" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0006295218301564</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bcp.2018.04.013" target="_blank" >10.1016/j.bcp.2018.04.013</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro

Popis výsledku v původním jazyce

Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transportermediated MDR using established in vitro methods. Our data showed accelerated ABCB1 inhibitor LY335979-sensitive, basolateral-to-apical transport of ribociclib across MDCKII-ABCB1 cell monolayers, which identified ribociclib as an ABCB1 substrate. The antiproliferative studies supported this finding by demonstrating significantly higher EC50 value in ABCB1-, but not ABCG2- or ABCC1-expressing MDCKII cells, than in the parent MDCKII cell line. Furthermore, we observed significant inhibitory effects of ribociclib on ABCB1 and ABCG2 transporters and CYP1A2, CYP3A4, CYP3A5, and CYP2C9 isoform activity in human CYP-expressing insect microsomes. The ribociclib induced ABCB1 and ABCG2 inhibition further reversed daunorubicin and mitoxantrone resistance in MDCKII and human MCF-7 breast carcinoma cell lines, indicating a synergistic anti-proliferative effect, without affecting ABCB1 or ABCG2 expression. In summary, our data indicate that ABCB1 affects ribociclib transport across the membranes and the high potential of ribociclib for drug-drug interactions (DDIs) through ABCB1 and ABCG2 transporters and CYP isoforms. Moreover, we demonstrate the beneficial MDR reversing potential of ribociclib, which could be further exploited in novel anticancer treatment strategies.

Název v anglickém jazyce

Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro

Popis výsledku anglicky

Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transportermediated MDR using established in vitro methods. Our data showed accelerated ABCB1 inhibitor LY335979-sensitive, basolateral-to-apical transport of ribociclib across MDCKII-ABCB1 cell monolayers, which identified ribociclib as an ABCB1 substrate. The antiproliferative studies supported this finding by demonstrating significantly higher EC50 value in ABCB1-, but not ABCG2- or ABCC1-expressing MDCKII cells, than in the parent MDCKII cell line. Furthermore, we observed significant inhibitory effects of ribociclib on ABCB1 and ABCG2 transporters and CYP1A2, CYP3A4, CYP3A5, and CYP2C9 isoform activity in human CYP-expressing insect microsomes. The ribociclib induced ABCB1 and ABCG2 inhibition further reversed daunorubicin and mitoxantrone resistance in MDCKII and human MCF-7 breast carcinoma cell lines, indicating a synergistic anti-proliferative effect, without affecting ABCB1 or ABCG2 expression. In summary, our data indicate that ABCB1 affects ribociclib transport across the membranes and the high potential of ribociclib for drug-drug interactions (DDIs) through ABCB1 and ABCG2 transporters and CYP isoforms. Moreover, we demonstrate the beneficial MDR reversing potential of ribociclib, which could be further exploited in novel anticancer treatment strategies.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GA16-26849S" target="_blank" >GA16-26849S: Interakce inhibitorů proteinových kináz s lékovými transportéry a biotransformačními enzymy; význam pro překonání rezistence v protinádorové terapii</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochemical Pharmacology

ISSN

0006-2952

e-ISSN

—

Svazek periodika

154

Číslo periodika v rámci svazku

August

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

8

Strana od-do

10-17

Kód UT WoS článku

000441369600002

EID výsledku v databázi Scopus

2-s2.0-85046338660