RT Journal Article
SR Electronic
T1 Interactions of alectinib with human ABC drug efflux transporters and CYP450 biotransformation enzymes: effect on pharmacokinetic multidrug resistance
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.086975
DO 10.1124/dmd.119.086975
A1 Jakub Hofman
A1 Ales Sorf
A1 Dimitrios Vagiannis
A1 Simona Sucha
A1 Eva Novotna
A1 Sarah Kammerer
A1 Jan-Heiner Kuepper
A1 Martina Ceckova
A1 Frantisek Staud
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/05/08/dmd.119.086975.abstract
AB Alectinib is a tyrosine kinase inhibitor currently used as a first-line treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). In the present work, we investigated possible interactions of this novel drug with ABC drug efflux transporters and cytochrome P450 (CYP) biotransformation enzymes that play significant roles in the phenomenon of multidrug resistance (MDR) of cancer cells as well as in pharmacokinetic drug-drug interactions. Using accumulation studies in MDCKII cells, alectinib was identified as an inhibitor of ABCB1 and ABCG2 but not of ABCC1. In subsequent drug combination studies, we demonstrated the ability for alectinib to effectively overcome MDR in ABCB1- and ABCG2-overexpressing MDCKII and A431 cells. To describe the pharmacokinetic interaction profile of alectinib in a complete fashion, its possible inhibitory properties toward clinically relevant CYP enzymes (i.e., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP3A5) were evaluated using human CYP-expressing insect microsomes, revealing alectinib as a poor interactor. Advantageously for its use in pharmacotherapy, alectinib further exhibited negligible potential to cause any changes in expression of ABCB1, ABCG2, ABCC1 and CYP1A2, CYP3A4, CYP2B6 in intestine, liver and NSCLC models. Our in vitro observations might serve as a valuable foundation for future in vivo studies that could support the rational for our conclusions and possibly enable providing more efficient and safer therapy to many oncological patients.SIGNIFICANCE STATEMENT N/A