Understanding the Critical Disposition Pathways of Statins to Assess Drug-Drug Interaction Risk During Drug Development: It's Not Just About OATP1B1
Understanding the Critical Disposition Pathways of Statins to Assess Drug-Drug Interaction Risk During Drug Development: It's Not Just About OATP1B1
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DOI：
10.1038/clpt.2012.163
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发表时间：
2012-11-01
影响因子：
6.7
通讯作者：
Fenner, K.
中科院分区：
文献类型：
--
作者：
Elsby, R.;Hilgendorf, C.;Fenner, K.
他汀类药物的使用在疾病领域广泛，因为许多患者患有合并症。鉴于这些药物已成为常见的合并用药，有必要了解他汀类药物和候选药物之间的药物相互作用（DDI）的潜在风险。尽管已知肝摄取转运蛋白有机阴离子转运多肽1B1（OATP 1B1）在他汀类药物相关DDI风险中发挥重要作用，但也可能涉及其他转运蛋白和代谢酶。因此，需要针对每种他汀类药物量身定制一种全面的风险评估方法。利用来自药物遗传学、DDI和有关人体吸收、分布、代谢和消除（ADME）的文献的证据，本综述确定了对每种他汀类药物的分布贡献最大、因此也是最关键的途径。它还提供了对如果抑制他汀类药物的处置，则全身暴露的预期理论最大增加的理解。最后，在逐个他汀类药物的基础上，我们建议在药物开发期间应常规进行体外抑制研究，以便更好地评估DDI风险。
The use of statins is widespread across disease areas because many patients have comorbidities. Given that these drugs have become common as comedications, it is essential to have an understanding of the potential risks of drug-drug interactions (DDIs) between statins and candidate drugs in development. Although the hepatic uptake transporter organic anion-transporting polypeptide 1B1 (OATP1B1) is known to play a substantial role in statin-related DDI risk, other transporters and metabolizing enzymes can also be involved. Consequently, a holistic approach to risk assessment is required, tailored to each statin. Using evidence from pharmacogenetics, DDIs, and literature on absorption, distribution, metabolism, and elimination (ADME) in humans, this review identifies pathways that contribute the most to, and are therefore the most critical to, the disposition of each statin. It also provides an understanding of the expected theoretical maximum increase in systemic exposure if the disposition of a statin is inhibited. Finally, on a statin-by-statin basis, we propose in vitro inhibition studies that should be routinely conducted during drug development so as to better assess DDI risk.