Gefitinib, an
epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of
topotecan, a substrate of the
ATP-binding cassette (
ABC) transporters P-glycoprotein (Pgp/MDR-1) and
breast cancer resistance
protein (BCRP/ABCG2). The effect of modulating these transporters on
topotecan penetration in
gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human
gliomas (U87 and MT330) and assessed
topotecan tumor ECF (tECF) penetration and the effect of
gefitinib on
topotecan tECF penetration and intratumor
topotecan distribution. We found that
topotecan penetration (P(
tumor)) of U87 was 0.96 +/- 0.25 (n = 7) compared with that of contralateral brain (P(contralateral), 0.42 +/- 0.11, n = 5; P = 0.001). In MT330
tumors, P(
tumor) (0.78 +/- 0.26, n = 6) and P(contralateral) (0.42 +/- 0.11, n = 5) also differed significantly (P = 0.013). Because both
tumor models had disrupted blood-brain barriers and similar P(
tumor) values, we used U87 and a steady-state
drug administration approach to characterize the effect of
gefitinib on
topotecan P(
tumor). At equivalent plasma
topotecan exposures, we found that P(
tumor) after
gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound
topotecan in
tumor (V(u,
tumor)) and found that it was significantly higher in groups receiving
gefitinib, implying that
gefitinib administration leads to a greater proportion of intracellular
topotecan. Our results provide crucial insights into the role that transporters play in central nervous system
drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer
drug distribution within a
tumor.