COMPARISON OF THE DRUG-DRUG INTERACTIONS POTENTIAL OF ERLOTINIB AND GEFITINIB VIA INHIBITION OF UDP-GLUCURONOSYLTRANSFERASES. Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] Journal article

We aimed to investigate and compare the effects of erlotinib and gefitinib on UDP-glucuronosyltransferase (UGT) activities, and to quantitatively evaluate their drug-drug interaction (DDI) potential due to UGT inhibition. The inhibitory effects of erlotinib and gefitinib on UGTs were determined using HPLC by measuring the formation rates for 4-methylumbelliferone (4-MU) glucuronide, imipramine N-glucuronide, and bilirubin glucuronides using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of erlotinib and gefitinib. Inhibition kinetic studies were conducted. AUC ratios were used to predict the risk of potential DDI in vivo. Erlotinib exhibited selective potent competitive inhibition against 4-MU glucuronidation by UGT1A1, and gefitinib demonstrated a wide range of inhibition against UGT-mediated 4-MU glucuronidation, particularly against UGT1A1, UGT1A7, UGT1A9 and UGT2B7. Erlotinib also exerted potent mixed inhibition against bilirubin glucuronidation in HLMs. We estimated that coadministration of erlotinib at 100 mg/day or higher doses may result in at least a 30% increase in the area under the curve (AUC) of drugs predominantly cleared by UGT1A1. Thus, the co-administration of erlotinib with drugs primarily cleared by UGT1A1 may result in potential DDI. In contrast, gefitinib is unlikely to cause a clinically significant DDI through inhibition of glucuronidation.

Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos]