Deng Feng, Sistonen Johanna, Neuvonen Mikko, Niemi Mikko
Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Basic Clin Pharmacol Toxicol. 2023 Oct;133(4):428-436. doi: 10.1111/bcpt.13928. Epub 2023 Aug 24.
Poly ADP-ribose polymerase (PARP) inhibitors have been approved for the treatment of various cancers. They share a 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 (IC ). 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 (IC 13.7 μM), followed by niraparib (42.6 μM) and olaparib (216 μM). 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.
聚 ADP - 核糖聚合酶（PARP）抑制剂已被批准用于治疗多种癌症。它们具有相似的作用机制，但在药代动力学特征和药物 - 药物相互作用（DDI）潜力方面存在差异。本研究评估了PARP抑制剂（尼拉帕利、奥拉帕利和卢卡帕利）与他汀类药物（阿托伐他汀和瑞舒伐他汀）之间潜在的ATP结合盒转运体介导的相互作用。我们使用囊泡转运试验研究了PARP抑制剂对乳腺癌耐药蛋白（BCRP）、多药耐药相关蛋白3（MRP3）和P - 糖蛋白（P - gp）的抑制活性，并确定了50%抑制所需的浓度（IC）。然后，我们使用机制静态模型预测了PARP抑制剂给药后他汀类药物暴露量的增加。卢卡帕利是BCRP介导的瑞舒伐他汀转运的最强抑制剂（IC为13.7 μM），其次是尼拉帕利（42.6 μM）和奥拉帕利（216 μM）。PARP抑制剂不影响MRP3。虽然尼拉帕利似乎抑制P - gp，但其抑制表现出很大的变异性。预计卢卡帕利、尼拉帕利和奥拉帕利对肠道BCRP的抑制分别会使瑞舒伐他汀的暴露量增加52%、37%和24%。PARP抑制剂与瑞舒伐他汀之间的相互作用单独来看可能临床意义不大，但与其他易感因素结合时，可能会增加瑞舒伐他汀相关不良反应的风险。
