1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterised in vitro.

2. Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalysed by CYP (fm,CYP) of 0.27 and 0.64, respectively. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3As (IC₅₀, 3.55, 12.9, 5.42, 41.6, and 17.2–22.9 µM [2 substrates], respectively), but not CYP2B6 or CYP2C8 (>190 µM). No time-dependent inhibition of any CYP was observed. In cultured human hepatocytes, rucaparib showed concentration-dependent induction of CYP1A2 mRNA and downregulation of CYP3A4 and CYP2B6 mRNA. In transfected cells expressing drug transporters, rucaparib was a substrate for P-gp and BCRP, but not for OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Rucaparib inhibited P-gp and BCRP (IC₅₀, 169 and 55 µM, respectively) and slightly inhibited OATP1B1, OATP1B3, OAT1, and OAT3 (66%, 58%, 58%, and 42% inhibition, respectively) at 300 µM. Rucaparib inhibited OCT1, OCT2, MATE1, and MATE2-K (IC₅₀, 4.3, 31, 0.63, and 0.19 μM, respectively).

3. DDI risk assessment using static models suggested potential CYP-related DDIs, with rucaparib as a perpetrator. Caution is advised when co-administering rucaparib with sensitive substrates of MATEs, OCT1, and OCT2.

1.聚的吸收，分布，代谢，清除和药物-药物相互作用（DDI）的电位（ADP-核糖）聚合酶（PARP）抑制剂rucaparib表征体外。

2. Rucaparib在人肝微粒体（HLM）中表现出中等的细胞渗透性，中等的人血浆蛋白结合（70.2％）和缓慢的代谢。在HLM中，细胞色素P450（CYP）1A2和CYP3A导致rucaparib代谢为其主要代谢物M324，其中CYP（fm，CYP）催化的代谢分数估计分别为0.27和0.64。Rucaparib可逆地抑制CYP1A2，CYP2C9，CYP2C19，CYP2D6和CYP3As（IC ₅₀，分别为3.55、12.9、5.42、41.6和17.2-22.9 µM [2个底物]，但不包括CYP2B6或CYP2C8（> 190 µM）。没有观察到任何CYP的时间依赖性抑制。在培养的人肝细胞中，rucaparib显示CYP1A2 mRNA的浓度依赖性诱导以及CYP3A4和CYP2B6 mRNA的下调。在表达药物转运蛋白的转染细胞中，rucaparib是P-gp和BCRP的底物，但不是OATP1B1，OATP1B3，OAT1，OAT3或OCT2的底物。Rucaparib抑制P-gp和BCRP（IC ₅₀在300μM分别169和55μM）和轻度抑制OATP1B1，OATP1B3，OAT1和OAT3（66％，58％，58％和42％抑制，分别地）。Rucaparib抑制OCT1，OCT2，MATE1和MATE2-K（IC ₅₀，4.3，31，0.63，和0.19μM，分别地）。

3.使用静态模型进行的DDI风险评估建议使用潜在的CYP相关DDI，并以rucaparib作为犯罪者。建议将rucaparib与MATE，OCT1和OCT2的敏感底物并用。