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.