Imatinib mode of action (DNB Dec 2011)
|A||Competetive inhibitor of bcr abl gene product|
|B||P glycoprotein inhibitor|
|C||P glycoprotein stimulator|
|D||Competitively antagonizes the ATP binding site|
Imatinib has inhibitory activity against ABL and its derivatives V-ABL, BCR-ABL and EVT 6-ABL. Inhibit the proliferation of myeloid cell lines that express BCR-ABL fusion proteins. Eg: associated with CML. Also inhibit proliferation of cells dependent on KIT/PDGFR for proliferation. These include mutant KIT associated with GIT tumours. ETV 6 PDGFR fusion associated with chronic myelomonocythic leukemia, FIP1 F1- PDGFR A associated with hypereosinophilic Syndrome.
- Chronic Myelomonocytic leukemia
- Hyper Eosinophilic syndrome
- Myelo fibrosis
- Prostatic carcinoma
Delayed: Myalgias, bone marrow suppression, edema, abnormal LFTs
- Treatment with SCH 66336, a farnesyl protein transferase inhibitor that has P-glycoprotein inhibitory action, enhanced the therapeutic efficacy of imatinib mesilate.
- Cells resistant to imatinib mesilate showed an overexpression of P-gp. it was reported that imatinib mesilate does not cross the blood-brain-barrier, that imatinib mesilate is a substrate of Pgp, and that this efflux transporter is an important determinant of the distribution of imatinib mesilate to the central nervous system
- This support the notion that imatinib mesilate is a substrate of Pgp. Imatinib's mechanism has action has got nothing to do with P-glycoprotein.
Note: Other TK inhibitors:
Geftinib, Erlotinib - both block intracellular component of EGFR, used in Ca-Iung.