Abstract：
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 (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 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.
摘要：
聚ADP-核糖聚合酶(PARP)抑制剂已被批准用于治疗各种癌症。它们有着相似的作用机制,但在药代动力学特征和潜在的药物-药物相互作用（DDI）方面存在差异。本研究评估了PARP抑制剂（尼拉帕尼，奥拉帕利,和rucaparib）和他汀类药物（阿托伐他汀和瑞舒伐他汀）。我们研究了PARP抑制剂对乳腺癌耐药蛋白（BCRP）的抑制活性，多药耐药相关蛋白3（MRP3），和P-糖蛋白（P-gp）使用囊泡转运测定法，并确定50％抑制所需的浓度（IC50）。然后，我们使用机械静态模型预测了PARP抑制剂给药后他汀类药物暴露量的增加.Rucaparib是BCRP介导的瑞舒伐他汀转运的最强抑制剂（IC5013.7μM），其次是尼拉帕尼（42.6μM）和奥拉帕尼（216μM）。PARP抑制剂不影响MRP3。虽然尼拉帕尼似乎抑制了P-gp，抑制表现出很大的变异性。rucaparib对肠道BCRP的抑制作用，预测尼拉帕尼和奥拉帕尼将瑞舒伐他汀暴露量提高52%，37%,24%,分别。PARP抑制剂和瑞舒伐他汀之间的相互作用可能仅具有较小的临床意义，但结合其他诱发因素,它们可能会增加瑞舒伐他汀相关不良反应的风险.
