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首页> 外文期刊>European journal of pharmaceutical sciences >Role of P-glycoprotein in the brain disposition of seletalisib: Evaluation of the potential for drug-drug interactions
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Role of P-glycoprotein in the brain disposition of seletalisib: Evaluation of the potential for drug-drug interactions

机译：p-糖蛋白在Seletalisib脑置入中的作用：评估药物 - 药物相互作用的潜力

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摘要

Seletalisib is an orally bioavailable selective inhibitor of phosphoinositide 3-kinase delta (PI3K delta) in clinical development for the treatment of immune-mediated inflammatory diseases. The present study investigated the role of P-gp in seletalisib disposition, especially brain distribution, and the associated risks of interactions. Seletalisib was found to be actively transported by rodent and human P-gp in vitro (transfected LLC-PK1 cells; K-m of ca. 20 mu M), with minimal or no affinity for the other tested transporters. A distribution study in knockout rats (single oral dosing at 750 mg kg(-1)) showed that P-gp restricts the brain disposition of seletalisib while having minimal effect on its intestinal absorption. Restricted brain penetration was also observed in cynomolgus monkeys (single oral dosing at 30 mg kg(-1)) using brain microdialysis and cerebrospinal fluid sampling (K-p(,uu) of 0.09 and 0.24, respectively). These findings opened the question of potential pharmacokinetic interaction between seletalisib and P-gp inhibitors. In vitro, CsA inhibited the active transport of seletalisib with an IC50 of 0.13 mu M. In rats, co-administration of high doses of CsA (bolus iv followed by continuous infusion) increased the brain distribution of seletalisib (single oral dosing at 5 mg kg(-1)). The observed data were found aligned with those predicted by in vitro-in vivo extrapolation. Based on the same extrapolation method combined with literature data, only very few P-gp inhibitors (i.e. CsA, quinine, quinidine) were predicted to increase the brain disposition of seletalisib in the clinical setting (maximal 3-fold changes).
机译：Seletalisib是一种口服生物生物可利用的磷酸钠3-激酶Delta（PI3K Delta）的临床开发，用于治疗免疫介导的炎性疾病。本研究调查了P-GP在Seletalisib处置，特别是脑分布的作用以及相关的相互作用风险。发现Seletalisib在体外（转染的LLC-PK1细胞中的人p-GP积极运输（转染的LLC-PK1细胞;约20μm），对其他测试的转运蛋白最小或没有亲和力。敲除大鼠的分布研究（750 mg kg（-1）的单个口服给药）表明，P-GP限制了Seletalisib的大脑置位，同时对其肠道吸收的影响最小。在Cynomolgus猴（单次口服给药以30mg Kg（-1））中也观察到受限制的脑渗透，使用脑微透析和脑脊液采样（分别为0.09和0.24的K-P（，uu））。这些发现开启了Seletalisib和P-GP抑制剂之间的潜在药代动力学相互作用问题。在体外，CSA抑制了Seletalisib的IC50，在大鼠中，在大鼠中，高剂量CSA（推注IV，随后连续输注）的共同施用（单次口服给药，5毫克kg（-1））。发现观察到的数据与通过体内外推预测的那些数据对齐。基于与文献数据相同的外推方法，预计只有很少的P-GP抑制剂（即CSA，奎宁，奎尼丁），以增加临床环境中Seletalisib的大脑置位（最大3倍变化）。

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