Systemic chemotherapy usually fails in the treatment of tumors in the central nervous system. Limited drug penetration into the target brain tumor tissue due to the presence of the blood-brain barrier (BBB) is generally considered to be a major cause of this lack of efficacy. The role of P-glycoprotein (Pgp) in the BBB is well established, especially by the use of Pgp knockout (KO) mice. More recently, the ABC half-transporter Breast Cancer Resistance Protein (BCRP) has been identified in the BBB but the impact of this transporter on the brain penetration of xenobiotics has not yet been so clearly defined. Topotecan is a cytotoxic drug and several reports have suggested that this compound appears to distribute relatively well into brain tissue and experimental brain tumors and clinical studies in patients with glioma or brain metastases have revealed a moderate but potentially useful activity of topotecan. Since topotecan is a substrate of both Pgp and BCRP we have investigated the role of P-gp and Bcrp on the brain penetration of topotecan by using wildtype (WT) mice, Mdr1a/Mdr1b DKO mice Bcrp1 KO, and in Mdr1a/Mdr1b/Bcrp1 TKO mice. Topotecan was administered i.v. to cohorts of mice and blood and tissues were sampled at 1, 4, 8 and 24 h after dosing. Topotecan levels were analyzed by HPLC. The AUCbrain in Mdr1a/Mdr1b DKO and in Bcrp1 KO mice was only 1.5-fold higher compared to WT mice. However, in Mdr1a/Mdr1b/Bcrp1 TKO mice where both transporters were absent the AUCbrain increased by 12-fold relative to WT mice. We verified that the very modest increase in Mdr1a/Mdr1b DKO was not due to increased expression of BCRP in the brain. The AUCplasma was 0.8, 2.5 and 4-fold higher in DKO, KO and TKO mice, respectively. By concomitant oral administration of the potent Pgp/BCRP dual inhibitor elacridar to WT, DKO and TKO mice (Bcrp1 KO not tested) we were able to increase the AUCbrain by 4.6, 4.4 and 16.9-fold, respectively, relative to WT mice receiving topotecan alone. The AUCplasma increased by 3.0, 3.1 and 5.1-fold, respectively. The topotecan levels in other tissues that were included in this analysis (e.g. liver, kidney, heart, lung, spleen) increased more or less proportional to the plasma levels. Our results show for the first time how two drug transporters by acting in concert limit the brain penetration of a substrate drug. Consequently, in order to improve the brain penetration of topotecan for targeting intracranial malignancies it is mandatory to use inhibitors of both drug transporters. Under the current conditions, the dual inhibitor elacridar inhibited Pgp and BCRP in the BBB of mice only partially.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]