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Dasatinib Pathway, Pharmacokinetics

PA166164906 Last updated March 2019 Caroline F. Thorn, Tahera Zabuawala.
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Conditions
31
Reactions
Dasatinib Pathway, Pharmacokinetics pathway diagram
Dasatinib Pathway, Pharmacokinetics — pathway diagram from PharmGKB / ClinPGx
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About this pathway

Background

Dasatinib is a tyrosine kinase inhibitor (TKI) approved by the US FDA to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in patients who are resistant or intolerant to imatinib [Article:17429625]. It also inhibits kinase activity of SRC family of kinases (SRC, LCK, HCK, YES1, FYN, BLK, LYN, FRK), KIT, PDGFRA and PDGFRB [Article:25709401].

Metabolism

Dasatinib is metabolized primarily in the liver. The main metabolites are M4, M5, M6, M20 and M24 [Articles:21827214, 18420784, 18556438]. M4 is formed by N-dealkylation with CYP3A4 the predominant catalyzing enzyme and some involvement of CYP1A1 and CYP1B1 [Article:18556438]. CYP3A4 is also the main enzyme responsible for hydroxylation to M20 and M24 (hydroxymethyl dasatinib) [Articles:21827214, 18556438]. M5, dasatinib n-oxide, is formed by oxidation primarily by FMO3 with various CYPs also capable of this reaction [Article:21827214]. It is unclear which enzymes form the M6 metabolite dasatinib carboxylic acid, possibly a cytosolic NAD-dependent oxidoreductase or an alcohol or aldehyde dehydrogenase [Article:18556438]. A glucuronide metabolite, also called M8, is also formed from dasatinb although the UGT enzymes involved have not been specified. An in vitro study showed dasatinib inhibition of UGT1A1, UGT1A9, and UGT2B15-driven glucuronidation of acetaminophen, suggesting that these enzymes may be the candidates responsible for dasatinib glucuronidation [Article:21235620].

Transport

Dasatinib can be exported by ABCB1 and ABCG2 in vitro [Articles:19785662, 17429625].

Reactions & interactions (31)

  • Biochemical Reaction
    dasatinib → dasatinib beta-d-glucuronide
  • Biochemical Reaction
    dasatinib → dasatinib carboxylic acid
  • Biochemical Reaction
    dasatinib → dasatinib n-oxide
  • Biochemical Reaction
    dasatinib → dasatinib M4
  • Biochemical Reaction
    dasatinib → dasatinib M20
  • Biochemical Reaction
    acetaminophen → acetaminophen glucuronide
  • Biochemical Reaction
    dasatinib → hydroxymethyl dasatinib
  • Catalysis
    UGT1A1 → Biochemical Reaction
  • Catalysis
    UGT1A9 → Biochemical Reaction
  • Catalysis
    UGT2B15 → Biochemical Reaction
  • Catalysis
    ABCB1 → Transport
  • Catalysis
    ABCG2 → Transport
  • Catalysis
    CYP2C9 → Biochemical Reaction
  • Catalysis
    FMO3 → Biochemical Reaction
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Catalysis
    CYP1A2 → Biochemical Reaction
  • Catalysis
    CYP1B1 → Biochemical Reaction
  • Catalysis
    CYP1A1 → Biochemical Reaction
  • Catalysis
    CYP1B1 → Biochemical Reaction
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Catalysis
    CYP3A5 → Biochemical Reaction
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Catalysis
    UGT1A9 → Biochemical Reaction
  • Catalysis
    UGT1A1 → Biochemical Reaction
  • Catalysis
    UGT2B15 → Biochemical Reaction
  • Catalysis
    CYP3A5 → Biochemical Reaction
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Inhibition
    dasatinib → UGT1A1
  • Inhibition
    dasatinib → UGT2B15
  • Inhibition
    dasatinib → UGT1A9
  • Transport
    dasatinib → dasatinib

Edit history (3)

  • 2017-05-30 Create
  • 2019-02-15 Update Updated to new illustrator formatting.
  • 2019-03-11 Approve
Dasatinib Pathway, Pharmacokinetics pathway diagram (enlarged)