P-Glycoprotein (ABCB1/MDR1) Controls Brain Penetration and Intestinal Disposition of the PARP1/2 Inhibitor Niraparib
| Autor: | Nancy H.C. Loos, Hilde Rosing, Margarida L. F. Martins, Maria C. Lebre, Danielle de Jong, Alfred H. Schinkel, Jos H. Beijnen, Matthijs M. Tibben, Sümeyra Mucuk |
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| Rok vydání: | 2021 |
| Předmět: |
Genetically modified mouse
Indazoles Abcg2 CYP3A Metabolite Pharmaceutical Science Pharmacology Poly(ADP-ribose) Polymerase Inhibitors Madin Darby Canine Kidney Cells chemistry.chemical_compound Mice Dogs Pharmacokinetics Piperidines Tetrahydroisoquinolines Drug Discovery Distribution (pharmacology) Animals Cytochrome P-450 CYP3A Tissue Distribution ATP Binding Cassette Transporter Subfamily B Member 1 CYP3A4 biology Chemistry Brain Biological Transport In vitro Intestines biology.protein Molecular Medicine Acridines |
| Zdroj: | Molecular pharmaceutics. 18(12) |
| ISSN: | 1543-8392 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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