The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate.
OBJECTIVE
It has been reported that the combination therapy of imatinib mesylate, a tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, is associated with remarkable antitumor activity in patients with recurrent glioblastoma multiforme. However, the mechanism of the added activity of hydroxyurea to imatinib is not known. The purpose of this study was to investigate in vitro, whether hydroxyurea could enhance the central nervous system penetration of imatinib, by inhibition of the ATP-dependent transporter proteins P-glycoprotein (ABCB1; MDR1; Pgp) and Breast Cancer Resistance Protein (ABCG2; BCRP), or by inhibition of cytochrome P450 3A (CYP3A) metabolism of imatinib.


METHODS
The effect of hydroxyurea on the Pgp and BCRP mediated transport of imatinib was investigated by the sulforhodamine-B (SRB) drug cytotoxicity assay and transepithelial transport assay. In vitro biotransformation studies with supersomes expressing human CYP3A4 were performed to investigate whether hydroxyurea inhibited CYP3A4.


RESULTS
In both in vitro cytotoxicity and transport assays, hydroxyurea did not affect Pgp and BCRP mediated transport of imatinib. In a biotransformation assay, hydroxyurea had no influence on the metabolic degradation of imatinib either.


CONCLUSIONS
The results indicate that hydroxyurea does not interact with imatinib by inhibition of Pgp and BCRP mediated transport or by CYP3A4 mediated metabolism of imatinib.
Oostendorp
Roos L
RL
Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Marchetti
Serena
S
Beijnen
Jos H
JH
Mazzanti
R
R
Schellens
Jan H M
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides; D001693:Biological Transport, Active / Q000187:drug effects*; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D051379:Mice; D009363:Neoplasm Proteins / Q000494:pharmacology*; D010879:Piperazines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A; D006918:Hydroxyurea