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
REFERENCES
Lagas JS, Sparidans RW, van Waterschoot RA, Wagenaar E, Beijnen JH, Schinkel AH. P-glycoprotein limits oral availability, brain penetration, and toxicity of an anionic drug, the antibiotic salinomycin. Antimicrob Agents Chemother. 2008;52:1034–9.
Zhou L, Schmidt K, Nelson FR, Zelesky V, Troutman MD, Feng B. The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in mice. Drug Metab Dispos. 2009;37:946–55.
Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, et al. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos. 2009;37:439–42.
Agarwal S, Sane R, Gallardo JL, Ohlfest JR, Elmquist WF. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther. 2010;334:147–55.
Kodaira H, Kusuhara H, Ushiki J, Fuse E, Sugiyama Y. Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther. 2010;333:788–96.
Poller B, Iusuf D, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics. Drug Metab Dispos. 2011;39:729–35.
Durmus S, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-GLYCOprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Mol Pharm. 2012;9:3236–45.
Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344:655–64.
Tang SC, Lagas JS, Lankheet NA, Poller B, Hillebrand MJ, Rosing H, et al. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer. 2012;130:223–33.
Iusuf D, Teunissen SF, Wagenaar E, Rosing H, Beijnen JH, Schinkel AH. P-glycoprotein (ABCB1) transports the primary active tamoxifen metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain penetration. J Pharmacol Exp Ther. 2011;337:710–7.
Lagas JS, Fan L, Wagenaar E, Vlaming ML, van Tellingen O, Beijnen JH, et al. P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 determine the pharmacokinetics of etoposide. Clin Cancer Res. 2010;16:130–40.
Lagas JS, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Hepatic clearance of reactive glucuronide metabolites of diclofenac in the mouse is dependent on multiple ATP-binding cassette efflux transporters. Mol Pharmacol. 2010;77:687–94.
Lin F, Marchetti S, Pluim D, Iusuf D, Mazzanti R, Schellens JH, et al. Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues. Clin Cancer Res. 2013;19:2084–95.
Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010;16:5664–78.
Taskar KS, Rudraraju V, Mittapalli RK, Samala R, Thorsheim HR, Lockman J, et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res. 2012;29:770–81.
Pestalozzi BC, Francis P, Quinaux E, Dolci S, Azambuja E, Gelber RD, et al. Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02–98 Trial. Ann Oncol. 2008;19:1837–41.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.
Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10:293–301.
Chalmers AJ, Lakshman M, Chan N, Bristow RG. Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. Semin Radiat Oncol. 2010;20:274–81.
Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011;5:387–93.
Leung M, Rosen D, Fields S, Cesano A, Budman DR. Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality. Mol Med. 2011;17:854–62.
Davar D, Beumer JH, Hamieh L, Tawbi H. Role of PARP inhibitors in cancer biology and therapy. Curr Med Chem. 2012;19:3907–21.
Rosen EM, Pishvaian MJ. Targeting the BRCA1/2 Tumor Suppressors. Curr Drug Targets. 2014;15:17–31.
Drew Y, Mulligan EA, Vong WT, Thomas HD, Kahn S, Kyle S, et al. Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2. J Natl Cancer Inst. 2011;103:334–46.
Drew Y, Plummer R. PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications. Drug Resist Updat. 2009;12:153–6.
Plummer R, Jones C, Middleton M, Wilson R, Evans J, Olsen A, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res. 2008;14:7917–23.
Plummer R, Lorigan P, Steven N, Scott L, Middleton MR, Wilson RH, et al. A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol. 2013;71:1191–9.
Sparidans RW, Durmus S, Schinkel AH, Schellens JH, Beijnen JH. Liquid chromatography-tandem mass spectrometric assay for the PARP inhibitor rucaparib in plasma. J Pharm Biomed Anal. 2014;88:626–9.
Lagas JS, van Waterschoot RA, van Tilburg VA, Hillebrand MJ, Lankheet N, Rosing H, et al. Brain accumulation of dasatinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by elacridar treatment. Clin Cancer Res. 2009;15:2344–51.
Poller B, Wagenaar E, Tang SC, Schinkel AH. Double-transduced MDCKII cells to study human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay in drug transport across the blood–brain barrier. Mol Pharm. 2011;8:571–82.
Murray J, Thomas H, Berry P, Kyle S, Patterson M, Jones C, et al. Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules. Br J Cancer. 2014;110:1977–84.
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–34.
Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer. 2003;10:43–73.
Yamada A, Ishikawa T, Ota I, Kimura M, Shimizu D, Tanabe M, et al. High expression of ATP-binding cassette transporter ABCC11 in breast tumors is associated with aggressive subtypes and low disease-free survival. Breast Cancer Res Treat. 2013;137:773–82.
Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell. 2004;6:129–37.
Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008;105:17079–84.
Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013;3:68–81.
Oostendorp RL, Buckle T, Beijnen JH, van Tellingen O, Schellens JH. The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Investig New Drugs. 2009;27:31–40.
Agarwal S, Uchida Y, Mittapalli RK, Sane R, Terasaki T, Elmquist WF. Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice. Drug Metab Dispos. 2012;40:1164–9.
Tang SC, de Vries N, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) gene dosage on plasma pharmacokinetics and brain accumulation of dasatinib, sorafenib, and sunitinib. J Pharmacol Exp Ther. 2013;346:486–94.
Lin F, de Gooijer MC, Moreno RE, Buil L, Christner SM, Beumer JH, et al. ABCB1, ABCG2 and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res. 2014;20:2703–13.
Oberoi RK, Mittapalli RK, Elmquist WF. Pharmacokinetic assessment of efflux transport in sunitinib distribution to the brain. J Pharmacol Exp Ther. 2013;347:755–64.
Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol. 2004;24:7612–21.
Potschka H, Fedrowitz M, Loscher W. Multidrug resistance protein MRP2 contributes to blood–brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003;306:124–31.
Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS. Breast cancer metastasis to the central nervous system. Am J Pathol. 2005;167:913–20.
Piura E, Piura B. Brain metastases from ovarian carcinoma. ISRN Oncol. 2011;2011:527453.
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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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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DOI: https://doi.org/10.1007/s11095-014-1442-z