Absorption and elimination of imatinib through the rat intestine in vitro.
Imatinib is a potent selective inhibitor of tyrosine kinases and is used primarily in the treatment of chronic myeloid leukemia and the gastrointestinal stromal tumour. Although, it is well established that imatinib is a substrate of several transport proteins which are also active in the intestinal mucosa, the mechanisms of imatinib intestinal absorption and elimination were not systematically investigated yet. To do that, we used a Sweetana-Grass type of diffusion chambers with segments of rat intestine as a model of the intestinal mucosa, measured the permeability coefficients of imatinib and its major metabolite (N-desmethyl imatinib) in both directions with and without specific and general inhibition of active transport, and calculated the efflux ratios. The results show that the good bioavailability of imatinib is highly likely achieved by its active absorption from the intestine and that its active elimination through the intestinal mucosa is mediated by a synergistic activity of organic cation transporter 1 in the basolateral membrane and the added activity of two efflux proteins (P-glycoprotein and breast cancer resistant protein) in the apical membrane of enterocytes of the rat ileum. Interestingly, it was found that N-desmethyl imatinib is only transported by P-glycoprotein.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Eva
E
Kralj
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia. Electronic address: simon.zakelj@ffa.uni-lj.si.
Simon
S
Zakelj
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Jurij
J
Trontelj
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Robert
R
Roškar
Department of Haematology, University Medical Center Ljubljana, Zaloška cesta 7, 1525 Ljubljana, Slovenia.
Peter
P
Cernelč
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Albin
A
Kristl
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001549:Benzamides / Q000493:pharmacokinetics*; D001692:Biological Transport; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism*; D010539:Permeability; D010879:Piperazines / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate
Active transport; Diffusion chambers; Imatinib; Intestinal absorption; Intestinal elimination