In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia

Br J Clin Pharmacol. 2004 Aug;58(2):212-6. doi: 10.1111/j.1365-2125.2004.02117.x.


Aims: To determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non-human species.

Methods: The blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using (14)C labelled compounds.

Results: The mean fraction of imatinib in plasma (f(p)) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, f(p) for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AML patients (90%). The unbound fraction of imatinib and CGP74588 in plasma was lower in rat, mouse, healthy humans and AML patients (2.3-6.5% at concentrations < or = 5000 ng ml(-1)) compared to monkey and dog (7.6-19%). Both compounds displayed high binding to human alpha(1)-acid glycoprotein. AML patients had a reduced haematocrit and showed greatest variability in their blood binding parameters.

Conclusion: Imatinib and CGP74588 displayed very similar blood binding parameters within all species/groups investigated. The five species clustered into two distinct groups with rat, mouse and humans being clearly different from dog and monkey. For both compounds, higher protein binding was associated with a decreased partitioning into blood cells.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / metabolism*
  • Benzamides
  • Dogs
  • Female
  • Humans
  • Imatinib Mesylate
  • Macaca fascicularis
  • Male
  • Mice
  • Middle Aged
  • Piperazines / blood
  • Piperazines / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / blood
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Protein Binding
  • Pyrimidines / blood
  • Pyrimidines / metabolism*
  • Rats
  • Rats, Wistar


  • Antineoplastic Agents
  • Benzamides
  • CGP 74588
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate