PURPOSE: 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. CONCLUSION: We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.
PURPOSE: 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. CONCLUSION: We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.
Authors: Richard A Larson; Ophelia Q P Yin; Andreas Hochhaus; Giuseppe Saglio; Richard E Clark; Hirohisa Nakamae; Neil J Gallagher; Eren Demirhan; Timothy P Hughes; Hagop M Kantarjian; Philipp D le Coutre Journal: Eur J Clin Pharmacol Date: 2011-12-30 Impact factor: 2.953
Authors: Francis J Giles; Ophelia Q P Yin; William M Sallas; Philipp D le Coutre; Richard C Woodman; Oliver G Ottmann; Michele Baccarani; Hagop M Kantarjian Journal: Eur J Clin Pharmacol Date: 2012-10-05 Impact factor: 2.953
Authors: Marcelo Moreira Tavares de Souza; Victor Van Vaisberg; Rodrigo Martins Abreu; Aline Siqueira Ferreira; Camila daSilvaFerreira; Paulo Dominguez Nasser; Helena Scavone Paschoale; Flair José Carrilho; Suzane Kioko Ono Journal: Medicine (Baltimore) Date: 2017-03 Impact factor: 1.889