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Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) Restrict Oral Availability and Brain Accumulation of the PARP Inhibitor Rucaparib (AG-014699)

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ABSTRACT

Background

Rucaparib is a potent, orally available, small-molecule inhibitor of poly ADP-ribose polymerase (PARP) 1 and 2. Ongoing clinical trials are assessing the efficacy of rucaparib alone or in combination with other cytotoxic drugs, mainly in breast and ovarian cancer patients with mutations in the breast cancer associated (BRCA) genes.

Purpose

We aimed to establish whether the multidrug efflux transporters ABCG2 (BCRP) and ABCB1 (P-gp, MDR1) affect the oral availability and brain penetration of rucaparib in mice.

Results

In vitro, rucaparib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse Abcg2. Transport could be inhibited by the small-molecule ABCB1 and ABCG2 inhibitors zosuquidar and Ko143, respectively. In vivo, oral availability (plasma AUC0–1 and AUC0–24) and brain levels of rucaparib at 1 and 24 h were increased by the absence of both Abcg2 and Abcb1a/1b after oral administration of rucaparib at 10 mg/kg.

Conclusions

Our data show to our knowledge for the first time that oral availability and brain accumulation of a PARP inhibitor are markedly and additively restricted by Abcg2 and Abcb1a/1b. This may have clinical relevance for improvement of rucaparib therapy in PARP inhibitor-resistant tumors with ABCB1 and/or ABCG2 expression and in patients with brain (micro)metastases positioned behind a functional blood–brain barrier.

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Abbreviations

AUC:

Area under the plasma concentration-time curve

BBB:

Blood–brain barrier

BCRP:

Breast cancer resistance protein

Cmax:

Maximum drug concentration in plasma

P-gp:

P-glycoprotein

SD:

Standard deviation

Tmax:

The time after administration of a drug when the maximum plasma concentration is reached

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank Anita Kort for critical reading and valuable contributions during the development of this manuscript. The research group of A.H. Schinkel receives revenue from commercial distribution of some of the mouse strains used in this study.

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Correspondence to Alfred H. Schinkel.

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Durmus, S., Sparidans, R.W., van Esch, A. et al. Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) Restrict Oral Availability and Brain Accumulation of the PARP Inhibitor Rucaparib (AG-014699). Pharm Res 32, 37–46 (2015). https://doi.org/10.1007/s11095-014-1442-z

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