Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction.

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Citation

Zhang T, Zhang K, Ma L, Li Z, Wang J, Zhang Y, Lu C, Zhu M, Zhuang X

Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction.

J Pharm Sci. 2018 Apr;107(4):979-983. doi: 10.1016/j.xphs.2017.12.007. Epub 2017 Dec 14.

PubMed ID
29247736 [ View in PubMed
]
Abstract

Icotinib is the first self-developed small molecule drug in China for targeted therapy of non-small cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction of icotinib were limited. By identifying metabolite generated in human liver microsomes and revealing the contributions of major cytochromes P450 (CYPs) in the formation of major metabolites, the aim of the present work was to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A liquid chromatography/UV/high-resolution mass spectrometer method was developed to characterize the icotinib metabolites. The formation of 6 major metabolites was studied in recombinant CYP isozymes and human liver microsomes with specific inhibitors to identify the CYPs responsible for icotinib metabolism. The metabolic pathways observed in vitro are consistent with those observed in human. Results demonstrated that the metabolites are predominantly catalyzed by CYP3A4 (77% approximately 87%), with a moderate contribution from CYP3A5 (5% approximately 15%) and CYP1A2 (3.7% approximately 7.5%). The contribution of CYP2C8, 2C9, 2C19, and 2D6 is insignificant. Based on our observations, to minimize drug-drug interaction risk in clinic, coprescription of icotinib with strong CYP3A inhibitors or inducers must be weighed. CYP1A2, a highly inducible enzyme in the smoking population, may also represent a determinant of pharmacokinetic and pharmacological variability of icotinib, especially in lung cancer patients with smoking history.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
IcotinibCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Details
IcotinibCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
IcotinibCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Inducer
Details