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Interactions of Cyclin-dependent Kinase Inhibitors with ABC Drug Transporters in vitro and in situ
Hofman, Jakub ; Štaud, František (advisor) ; Wsól, Vladimír (referee) ; Kryštof, Vladimír (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Jakub Hofman Supervisor: Prof. PharmDr. František Štaud, Ph.D. Title of Doctoral Thesis: Interactions of cyclin-dependent kinase inhibitors with ABC drug transporters in vitro and in situ In the present work, we focused on the study of pharmacokinetic interactions of cyclin-dependent kinase inhibitors (CDKi) with drug efflux transporters breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Using accumulation and transport methods with MDCKII-ABCG2 cells, we showed purvalanol A, olomoucine II, bohemine and roscovitine to inhibit BCRP. Employing accumulation method with MDCKII-ABCB1 cells, we further observed that purvalanol A potently inhibits P-gp and partial inhibition was recorded in the case of other studied CDKi (olomoucine II, roscovitine, flavopiridol, SNS-032). Transport method with the same cellular models was used for the study of substrate affinity of olomoucine II and purvalanol A when olomoucine II was determined to be a dual P-gp and BCRP substrate. Substrate affinity of purvalanol A toward any of the transporters tested was not observed. These findings were confirmed by the ATPase vesicular assay and using this experimental setup, we further...
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