Theoretical study on the mechanism of N- and α-carbon oxidation of lapatinib catalyzed by cytochrome P450 monooxygenase

  • Hong Huang
  • Xue Bai
  • Lijun YangEmail author
Original Paper


Lapatinib, an orally active dual tyrosine kinase inhibitor, is efficacious in combination therapy with capecitabine for advanced metastatic breast cancer. Despite its importance, it has been associated with hepatotoxicity observed in clinical trials and postmarketing surveillance. The mechanisms of hepatotoxicity at the chemical and cellular levels may link to drug metabolism. In this study, the N- and α-carbon oxidation processes of lapatinib catalyzed by CYP3A4 were explored by density functional theory method. The calculation results show that oxidation of C6 is the primary metabolic process and carboxylic acid is the main metabolic product. Both hydroxylation of C8 and subsequent formation of primary amines are feasible. However, it is not easy for the primary amines to form active metabolites nitroso, which indicates that there are other paths for the production of nitroso. Carboxylic acid is not the main metabolite of N7 oxidation because of higher hydrolysis energy barrier of intermediate nitrone. It is worthy to study subsequent N-hydroxylation and its downstream reaction, which may be the main pathway for the formation of nitroso. These results lay the foundation for drug design and optimization.


Density functional theory Lapatinib N- and α-carbon oxidation Active metabolite 



The authors also acknowledge the State Key Laboratory of Biotherapy and Cancer Center (Sichuan University) for the use of computing facilities.

Funding information

This work is based on research supported by the Meritocracy Research Funds of China West Normal University (17YC037).

Supplementary material

894_2019_4125_MOESM1_ESM.pdf (1.4 mb)
ESM 1 (PDF 1409 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Chemical Synthesis and Pollution Control Key Laboratory of Sichuan ProvinceChina West Normal UniversityNanchongPeople’s Republic of China

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