The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1.
OBJECTIVE
Inhibition of the UDP-glucuronosyltransferase (UGT) 1A1 by nilotinib was examined in vitro with SN-38 as a substrate, to estimate the possibility of drug-drug interaction of nilotinib with other medicines predominantly detoxified by UGT1A1.


METHODS
Inhibition of UGT1A1-catalyzed SN-38 glucuronidation by nilotinib was examined with human liver microsomes (HLM) and recombinant human UGT1A1 as enzyme sources. Inhibition constants (K(i)) were estimated with kinetic analysis.


RESULTS
Nilotinib potently inhibited the SN-38 glucuronidation by human liver microsomal UGT1A1 and recombinant UGT1A1 in a noncompetitive manner, with K(i) values of 0.286 ± 0.0094 and 0.079 ± 0.0029 μM, respectively. If a drug that serves as a substrate of UGT1A1 is administered with nilotinib, the area under the plasma concentration-time curve of a drug estimated by using these K(i) values would be two times or higher than that without nilotinib, suggesting drug-drug interactions involving UGT1A1. These in vitro data and the prediction of drug-drug interaction are helpful for the clinical management of the nilotinib use.


CONCLUSIONS
We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.
Fujita
Ken-ichi
K
Department of Medical Oncology, International Medical Center, Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. fujitak@saitama-med.ac.jp
Sugiyama
Minako
M
Akiyama
Yuko
Y
Ando
Yuichi
Y
Sasaki
Yasutsuna
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D055815:Young Adult; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000099148:UGT1A1 Enzyme; C498826:nilotinib