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The UGT1A1*28 polymorphism correlates with erlotinib's effect on SN-38 glucuronidation
Yong Liu1, Jacqueline Ramírez, Larry House
1Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
European Journal of Cancer (Oxford, England : 1990)
|June 29, 2010
Summary
Erlotinib significantly inhibits SN-38 glucuronidation by UGT1A1, increasing irinotecan
Area of Science:
- Pharmacology
- Drug Metabolism
- Genetics
Background:
- Irinotecan and erlotinib combination therapy shows significant toxicity.
- SN-38 glucuronidation is a key metabolic pathway for irinotecan's active metabolite.
- UGT1A polymorphisms influence drug metabolism and potential drug-drug interactions.
Purpose of the Study:
- To investigate erlotinib's effect on SN-38 glucuronidation.
- To explore the association between UGT1A polymorphisms and SN-38 glucuronidation activity in the presence of erlotinib.
- To predict the risk of drug-drug interactions (DDI) between erlotinib and irinotecan.
Main Methods:
- Measured SN-38 glucuronidation rates using recombinant UGT1A1 and human liver microsomes.
- Assessed erlotinib's inhibitory effect on SN-38 glucuronidation kinetics.
- Used pharmacokinetic parameters to predict in vivo drug-drug interactions and AUC ratios.
Main Results:
- Erlotinib demonstrated potent non-competitive inhibition of SN-38 glucuronidation via UGT1A1.
- Predicted a potential increase of at least 24% in SN-38 AUC with erlotinib doses ≥50mg/day.
- Observed significant correlation between SN-38 glucuronidation activity and UGT1A1*28 polymorphism.
Conclusions:
- Erlotinib is a potent UGT1A1 inhibitor, significantly impacting SN-38 glucuronidation.
- Coadministration of erlotinib with irinotecan may lead to clinically significant drug-drug interactions.
- UGT1A1*28 polymorphism influences the interaction between erlotinib and SN-38 metabolism.
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