P-Glycoprotein (ABCB1/MDR1) Controls Brain Penetration and Intestinal Disposition of the PARP1/2 Inhibitor Niraparib

Abstract

Niraparib (Zejula), a selective oral PARP1/2 inhibitor registered for ovarian, fallopian tube, and primary peritoneal cancer treatment, is under investigation for other malignancies, including brain tumors. We explored the impact of the ABCB1 and ABCG2 multidrug efflux transporters, the OATP1A/1B uptake transporters, and the CYP3A drug-metabolizing complex on oral niraparib pharmacokinetics, using wild-type and genetically modified mouse and cell line models. In vitro, human ABCB1 and mouse Abcg2 transported niraparib moderately. Compared to wild-type mice, niraparib brain-to-plasma ratios were 6- to 7-fold increased in Abcb1a/1b –/– and Abcb1a/1b;Abcg2–/– but not in single Abcg2–/– mice, while niraparib plasma exposure at later time points was ∼2-fold increased. Niraparib recovery in the small intestinal content was markedly reduced in the Abcb1a/1b-deficient strains. Pretreatment of wild-type mice with oral elacridar, an ABCB1/ABCG2 inhibitor, increased niraparib brain concentration and reduced small intestinal content recovery to levels observed in Abcb1a/1b;Abcg2–/– mice. Oatp1a/1b deletion did not significantly affect niraparib oral bioavailability or liver distribution but decreased metabolite M1 liver uptake. No significant effects of mouse Cyp3a ablation were observed, but overexpression of transgenic human CYP3A4 unexpectedly increased niraparib plasma exposure. Thus, Abcb1 deficiency markedly increased niraparib brain distribution and reduced its small intestinal content recovery, presumably through reduced biliary excretion and/or decreased direct intestinal excretion. Elacridar pretreatment inhibited both processes completely. Clinically, the negligible role of OATP1 and CYP3A could be advantageous for niraparib, diminishing drug–drug interaction or interindividual variation risks involving these proteins. These findings may support the further clinical development and application of niraparib.

Transporter‑mediated drug‑drug interactions involving poly (ADP‑ribose) polymerase inhibitors (Review)

“…The five PARP inhibitors are substrates for P-gp and BRCP. In a DDI study, P-gp and BRCP inhibitors did not have any significant impact on the systemic exposure of olaparib, niraparib and veliparib, but significantly increased their brain accumulation, indicating that P-gp and BRCP inhibitors may improve treatment outcomes when co-administered with olaparib, niraparib or veliparib in patients with brain tumors (34,37,57). For rucaparib and talazoparib, P-gp and BRCP have critical roles in their systemic exposure and brain accumulation, indicating that dose adjustment or caution is required when rucaparib and talazoparib are co-administered with strong P-gp and BRCP inhibitors or inducers (43,51,52).…”

“…Niraparib is a substrate for P-gp and BCRP; its major primary metabolite M1 is a substrate for MATE1 and MATE2-K (37). In vitro studies have indicated that P-gp and BCRP do not have any significant impact on the bioavailability and liver disposition of niraparib (37). However, P-gp and BCRP may significantly increase the brain distribution of niraparib.…”

“…In a study conducted in mice, co-administration of elacridar significantly increased the brain concentration of niraparib without significantly altering the plasma concentration (38). Therefore, P-gp and BCRP inhibitors may increase the brain concentration of niraparib, improving the treatment outcome in patients with brain tumors (37)(38)(39). However, close monitoring of adverse reactions [e.g., hematotoxicity, palpitations, gastrointestinal toxicities, mucositis, aspartate aminotransferase (AST) alanine aminotransferase (ALT) elevation, urinary tract infection and rash] is required when niraparib is administered concomitantly with P-gp and BCRP inhibitors.…”

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies

“…The relationship between the two was first discovered by Rottenberg et al The group’s experiments demonstrated that in a breast tumor model, the emergence of PARPi-acquired resistance is related to upregulation of P-gp expression, and that the P-gp inhibitor tariquidar can reverse its overexpression ( Rottenberg et al, 2008 ). Similarly, in vitro experiments by Margarida et al demonstrated that ABCB 1a/1b attenuated brain penetration and promoted systemic elimination of niraparib in mice, with partial reversal of resistance following treatment with the ABCB1 inhibitor Elacridar (F. Martins et al, 2021 ). A clinical study (NCT02681237) found that ABCB1 was upregulated in 15% of patients in the progression group after using PARPi.…”

“…It has a very wide substrate specificity, and it is highly expressed in many tumors, especially in drug-resistant breast cancer and OC ( Christie et al, 2019 ). With the up-regulation of ABCB 1a/1b genes, the expression of P-gp efflux transporter increases, resulting in a decrease in the effective intracellular drug concentration, thus, leading to PARPi resistance (F. Martins et al, 2021 ). In 2020, a quantitative mass spectrometry imaging (LC-MS/MS) assay showed that in a P-gp-overexpressing ovarian cancer model, niraparib was unevenly distributed within the tumor, reducing the efficacy of drug treatment; thus, suggesting that it is resistant to PARPi( Morosi et al, 2020 ).…”