Comparison of the Drug-Drug Interactions Potential of Erlotinib and Gefitinib via Inhibition of UDP-Glucuronosyltransferases

Abstract

ABSTRACT: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 high-performance liquid chromatography 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. Area under the curve (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 AUC of drugs predominantly cleared by UGT1A1. Thus, the coadministration 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.Erlotinib and gefitinib are potent, reversible, and selective inhibitors of the tyrosine kinase of the epidermal growth factor receptor. Both drugs have been approved for the treatment of patients with non-small-cell lung cancer, and erlotinib is also indicated for pancreatic cancer. In addition, phase II trials have suggested activity for these agents in a number of other solid tumors (Sequist and Lynch, 2008). Gefitinib and erlotinib share a common chemical backbone structure and exhibit similar oral bioavailability and disposition characteristics in humans after oral administration (Siegel-Lakhai et al., 2005).Drug-drug interactions (DDI) have received increasing attention over the past few decades. Several DDIs were reported to be associated with erlotinib and gefitinib. Coadministration of erlotinib has been reported to enhance the carboplatin exposure (Patnaik et al., 2006) and increase the serum concentration of phenytoin (Grenader et al., 2007). Drug interactions were also observed in two patients who received both gefitinib and warfarin simultaneously, which resulted in an enhancement of the warfarin effect (Onoda et al., 2005). Combination of gefitinib with capecitabine and radiation in patients with pancreatic and rectal cancer (Czito et al., 2006), as well as the combination of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer (Veronese et al., 2005), are associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level.Metabolizing enzyme-based DDI constitute the major pro...

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

“…Thus, in this research, the unbound portal vein concentration (0.16, 0.18, and 0.31 μmol/L) was used for the reversible inhibition portion (for 50, 100, and 150 mg/d doses, respectively), while the unbound systemic concentration (0.07, 0.19, and 0.13 μmol/L) was adopted to avoid over-prediction of irreversible inactivation [30] . The values for [I] in vivo were derived from references [17,31] . A k deg(CYP3A) of 0.000321 min -1 was adopted, in accordance with Obach et al [27] .…”

“…The inhibition of other isoforms by erlotinib was not time and NADPH dependent (data not shown). 19 μmol/L were adopted to avoid over-prediction for three oral doses [17] . With a K I, u and a k inact of erlotinib for probe substrates midazolam, testosterone and …”

“…A k deg(CYP3A) of 0.000321 min -1 was adopted, in accordance with Obach et al [27] . The values of f m(CYP3A) and f m(CYP2C8) were arbitrarily set to be 0.1-1 to predict the DDI risk for all possible coadministered drugs [17] .…”

“…Inhibition constant (K i ) values were determined by incubating various probe substrates (5-50 μmol/L paclitaxel, 30-100 μmol/L testosterone or 5-50 μmol/L nifedipine) in the presence or absence of erlotinib. K i values were calculated by nonlinear regression using the equations for competitive inhibition (eq 1), noncompetitive inhibition (eq 2), or mixed inhibition (eq 3) [17] . .…”

“…Nevertheless, in a cell-based CYP3A activity assay, erlotinib was shown to decrease the formation of 1'-hydroxymidazolam, showing the potency to inhibit CYP3A activity [16] . As for the phase II enzymes, erlotinib was shown to exhibit inhibition activity on human UDP-glucuronosyltransferase (UGT) 1A1 [17] . The effects of erlotinib on other phase I CYP isoforms are still unknown.…”