Modulation of adenosine triphosphate binding cassette transporters has differential effects on central nervous system penetration of camptothecin analogs

Topotecan and irinotecan are camptothecin analogs with considerable promise to treat primary CNS tumors. Since these compounds are substrates for adenosine triphosphate (ATP)-binding cassette (ABC) transporters, their CNS penetration may be regulated by these transporters, which are expressed at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB). The tyrosine kinase inhibitor gefitinib interacts with multiple ABC transporters such as P-gp and BCRP in vitro, suggesting it could modulate CNS transporters. The major objective of our work is to determine the brain parenchymal ECF and ventricular CSF (vCSF) penetration of topotecan, and the effect of gefitinib on brain ECF and vCSF penetration of topotecan. After 4 and 8 mg/kg topotecan injection in mice, the brain ECF:plasma AUC ratio of unbound topotecan lactone was 0.21+/-0.04 and 0.61+/-0.16, respectively; the vCSF:plasma AUC ratio was 1.18+/-0.10 and 1.30+/-0.13, respectively. Oral gefitinib administration (200 mg/kg) one hour before 4 mg/kg topotecan injection, significantly increased the brain ECF:plasma AUC ratio of topotecan lactone (1.6-fold) compared to control (P<0.05). In contrast, the vCSF:plasma topotecan AUC ratio decreased to 0.98+/-0.05 with gefitinib (P<0.05). Bcrp1 was detected at the apical side of the choroid plexus in mice, suggesting an influx pump for topotecan.; In preparation to conduct studies of the CNS penetration of irinotecan and SN-38, we studied the interaction between SN-38, an active metabolite of irinotecan, and MRP4. Results of our intracellular accumulation and cytotoxicity studies suggest that SN-38 is a substrate for MRP4 and that gefitinib can modulate MRP4 activity in vitro. Despite in vitro data showing an interaction between SN-38 and MRP4, in vivo pharmacokinetics studies showed minimum effect of MRP4 on the systemic disposition of irinotecan and SN-38. These results and the methodologies developed will be applied in future studies of the CNS penetration of irinotecan in the mouse model.; In conclusion, our results show that modulation of ABC transporters at the BBB and BCB exhibit differential effects on topotecan CNS penetration. Caution must be taken in combining tyrosine kinase inhibitors with anticancer drugs, since this may not necessarily enhance the CSF drug penetration of drugs that are substrates for influx transporters.