The tyrosine kinase inhibitors (TKIs) and multikinase inhibitors (MKIs) are oncology drugs of increasing importance that have improved the treatment of multiple tumors types. In some patients these agents produce adverse effects, including pharmacokinetic drug-drug interactions, due to cytochrome P450 (CYP) inhibition. Information on the propensity of the drugs to elicit such effects often only becomes evident as the drugs enter clinical use. The present study assessed 18 kinase inhibitors (1 and 50 μM) for the inhibition of major drug metabolizing CYPs 1A2, 2C9, 2D6 and 3A4 in human liver microsomes. Most TKIs and MKIs inhibited CYP reactions at the higher concentration but axitinib also potently inhibited CYP1A2-dependent 7-ethoxyresorufin O-deethylation activity at the lower concentration. Kinetic analyses of CYP1A2 inhibition by axitinib were undertaken in microsomes and found a Ki of 0.11 ± 0.01 μM, which was 7.5-fold lower than the Km for 7-ethoxyresorufin oxidation (0.83 ± 0.06 μM); the inhibition mechanism was linear-mixed. From computational modeling two potential binding modes for axitinib were identified in the active site of CYP1A2: one in which the oxidizable axitinib thioether sulfur atom is within ~4.45 Å of the CYP1A2 heme, and is likely to favor biotransformation of the drug, and a second in which the pyridine moiety is in proximity to the heme, which may contribute to inhibition. The applicability of these findings to potential pharmacokinetic interactions in patients during axitinib treatment should now be assessed.
Keywords: 7-Ethoxyresorufin (PubChem CID: 3294); Axitinib; Axitinib (PubChem CID: 6450551); CYP1A2 inhibitor; Cediranib (PubChem CID: 9933475); Cytochrome P450; Imatinib (PubChem CID: 5291); Linifanib (PubChem CID: 11485656); Molecular modeling; Motesanib (PubChem CID: 11667893); Multikinase inhibitor; Neratinib (PubChem CID: 9915743); Nilotinib (PubChem CID: 644241).
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