Inhibition of efflux transporters by poly ADP-ribose polymerase inhibitors

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Abstract Poly ADP-ribose polymerase (PARP) inhibitors have been approved for the treatment of various cancers. They share similar mechanism of action, but have differences in pharmacokinetic characteristics and potential for drug-drug interactions (DDI). This study evaluated the potential ATP-binding cassette transporter-mediated interactions between PARP inhibitors (niraparib, olaparib, and rucaparib) and statins (atorvastatin and rosuvastatin). We studied the inhibitory activity of PARP inhibitors on breast cancer resistance protein (BCRP), multidrug resistance-associated protein 3 (MRP3), and P-glycoprotein (P-gp) using vesicular transport assays and determined the concentrations required for 50% inhibition (IC50). Then, we predicted the increase of statin exposure followed by the administration of PARP inhibitors using a mechanistic static model. Rucaparib was the strongest inhibitor of BCRP-mediated rosuvastatin transport (IC50 13.7 ?M), followed by niraparib (42.6 ?M) and olaparib (216 ?M). PARP inhibitors did not affect MRP3. While niraparib appeared to inhibit P-gp, the inhibition showed large variability. The inhibition of intestinal BCRP by rucaparib, niraparib and olaparib was predicted to elevate rosuvastatin exposure by 52%, 37%, and 24%, respectively. The interactions between PARP inhibitors and rosuvastatin are probably of minor clinical significance alone, but combined with other predisposing factors they may increase the risk of rosuvastatin-associated adverse effects.
Originalspråkengelska
TidskriftBasic & Clinical Pharmacology & Toxicology
Volym133
Nummer4
Sidor (från-till)428-436
Antal sidor9
ISSN1742-7835
DOI
StatusPublicerad - okt. 2023
MoE-publikationstypA1 Tidskriftsartikel-refererad

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