About this pathway
Background
Nilotinib is a small molecule tyrosine kinase inhibitor and a derivative of imatinib. It is used in the treatment of chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) [Article:21827214].
Metabolism
Unchanged nilotinib is the main circulating form of the drug in serum [Article:20702754]. Nilotinib has a half-life of approximately 17 hours with greater than 90% eliminated in feces [Article:18765523]. Its mean clearance in patients with newly diagnosed Ph+ CML in chronic-phase was 20.2l/h [Article:18765523].
Nilotinib is metabolized by oxidation and hydroxylation, mainly by CYP3A4 [Article:20702754]. Some papers suggest that CYP2C8 plays a minor role although primary data was not shown [Article:21827214]. In studies of healthy volunteers given nilotinib alone or in combination with rifampicin (a CYP3A4 inducer) and ketoconazole (a CYP3A4 inhibitor), rifampicin increased clearance of nilotinib around 5-fold and ketoconazole increased exposure of nilotinib and increased the occurrence of side effects [Article:20702754]. No nilotinib metabolites contribute to its pharmacological activity [Article:21827214]. Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 [Article:18765523].
Nilotinib can be transported by both ABCB1 and ABCG2 [Article:19785662]. In one in vitro system, overexpression of ABCG2 protected cells from nilotinib toxicity, whereas overexpression of ABCB1 only slightly decreased nilotinib toxicity [Article:19785662]. However in a different in vitro system using transporter specific inhibitors and different concentrations of nilotinib, ABCB1 was considered the main tranporter with ABCG2 having lesser role [Article:22845311].
Pharmacodynamics
Nilotinib inhibits BCR-ABL in a similar manner to imatinib [Article:15710326]. It reversibly and selectively binds to the ATP-binding site of the inactive conformation of ABL with a greater affinity than imatinib. This stabilizes the inactive conformation, with the activation loop of the ABL protein in an inactive ‘DFG out’ conformation, similar to that observed in the imatinib-ABL complex [Articles:15710326, 16000593]. In a phase I study of 33 patients with imatinib-resistant CML, 51 ABL mutations were observed [Article:16775235]. Nilotinib was active in patients with or without those mutations. However, no significant difference in response rates was observed between the two groups. Only two patients with T315I mutation had no response to nilotinib treatment. In addition to BCR-ABL, nilotinib also inhibits kinases PDGFRA, PDGFRB and KIT [Article:18765523].
Common adverse events associated with nilotinib were myelosuppression, transient indirect hyperbilirubinemia and rashes. Nilotinib is also associated with a prolonged cardiac ventricular repolarization, as seen with an increase in corrected QT interval (QTc) [Article:21861543].
Reactions & interactions (17)
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Biochemical Reaction
nilotinib → nilotinib n-oxide
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Biochemical Reaction
nilotinib → nilotinib carboxylic acid
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Catalysis
CYP3A4 → Biochemical Reaction
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Catalysis
ABCG2 → Transport
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Catalysis
ABCB1 → Transport
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Inhibition
nilotinib → ABCB1
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Inhibition
nilotinib → PDGFRA
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Inhibition
nilotinib → CYP2C8
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Inhibition
nilotinib → PDGFRB
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Inhibition
nilotinib → BCR-ABL
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Inhibition
nilotinib → KIT
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Inhibition
nilotinib → CYP3A4
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Inhibition
nilotinib → CYP2D6
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Inhibition
nilotinib → UGT1A1
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Inhibition
nilotinib → CYP2C9
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Transport
nilotinib → nilotinib
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Transport
nilotinib → nilotinib
Edit history (2)
- 2018-04-04 Create
- 2019-02-20 Update Updated to new illustrator formatting.