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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant UO1-GM61393] (Pharmacogenetics of Anticancer Agents Research Group).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029660
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- DDI
- drug-drug interactions
- UGT
- UDP-glucuronosyltransferase
- HLMs
- human liver microsomes
- AUC
- area under the curve
- OSI-774
- N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine
- 4-MU
- 4-methylumbelliferone
- 4-MUG
- 4-methylumbelliferone-d-glucuronide
- UDPGA
- uridine 5′-diphosphoglucuronic acid
- HPLC
- high-performance liquid chromatography.
- Received July 22, 2009.
- Accepted October 21, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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