Journal
MOLECULAR PHARMACEUTICS
Volume 18, Issue 12, Pages 4371-4384Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.1c00553
Keywords
niraparib; PARP1/2 inhibitor; P-glycoprotein/ABCB1; brain penetration; intestinal disposition; oral availability
Funding
- Di-AcetylM BV (Amsterdam, the Netherlands)
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The study found that Abcb1 deficiency significantly increased the distribution of niraparib in the brain and reduced its recovery in the small intestine, which was completely inhibited by Elacridar pretreatment. OATP1 and CYP3A had minimal impact on the metabolism and distribution of niraparib, which could be advantageous in reducing the risk of drug-drug interactions or interindividual variation.
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 similar to 2-fold increased. Niraparib recovery in the small intestinal content was markedly reduced in the Abcb1a/1b-deficient strains. Pretreatment of wildtype 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.
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