Organic Anion Transporter 2-Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability-Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs
Organic Anion Transporter 2-Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability-Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs
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DOI：
10.1124/jpet.118.252049
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发表时间：
2018-11-01
影响因子：
3.5
通讯作者：
Varma, Manthena V. S.
中科院分区：
文献类型：
--
作者：
Kimoto, Emi;Mathialagan, Sumathy;Varma, Manthena V. S.
高渗透性低分子量酸/两性离子[即，扩展清除分类系统1A类（ECCS 1A）药物]被认为是通过代谢清除的，膜转运蛋白在其肝脏清除中的作用最小。然而，这些药物的肝清除率在体外-体内（IVIV）转化中经常出现明显的脱节。使用人肝微粒体和原代肝细胞测量的代谢率往往预测不足。在此，我们评估了有机阴离子转运蛋白2（OAT 2）介导的肝脏摄取在ECCS 1A药物清除中的作用。对于一组25种ECCS 1A药物，使用转运蛋白转染的细胞和原代人肝细胞评估体外转运活性。除两种药物外，所有药物均显示出对OAT 2的底物亲和力，而四种药物（溴芬酸、恩他卡朋、荧光素和那格列奈）在转染细胞中也显示出OATP 1B 1活性。这些药物中的大多数（25种中的21种）显示出被平板培养的人肝细胞主动摄取，利福霉素SV（泛转运蛋白抑制剂）使摄取减少约25%-95%。在一些药物在肝微粒体孵育中未显示可测量的底物消耗后，估计了19种药物的代谢转换。评价了使用体外数据的IVIV外推法，以预测OAT 2单独底物的人肝清除率，考虑1）仅摄取转运，2）仅代谢，3）转运蛋白-酶相互作用（扩展清除模型）。与其他两种方法相比，转运蛋白-酶相互作用方法实现了提高的预测准确性（平均误差倍数= 1.9和偏差= 0.93）。总之，本研究为OAT 2介导的肝脏摄取在确定几种临床重要ECCS 1A药物的药代动力学中的作用提供了功能性证据。
High-permeability-low-molecular-weight acids/zwitterions [i.e., extended clearance classification system class 1A (ECCS 1A) drugs] are considered to be cleared by metabolism with a minimal role of membrane transporters in their hepatic clearance. However, a marked disconnect in the in vitro-in vivo (IVIV) translation of hepatic clearance is often noted for these drugs. Metabolic rates measured using human liver microsomes and primary hepatocytes tend to underpredict. Here, we evaluated the role of organic anion transporter 2 (OAT2)-mediated hepatic uptake in the clearance of ECCS 1A drugs. For a set of 25 ECCS 1A drugs, in vitro transport activity was assessed using transporter-transfected cells and primary human hepatocytes. All but two drugs showed substrate affinity to OAT2, whereas four (bromfenac, entacapone, fluorescein, and nateglinide) also showed OATP1B1 activity in transfected cells. Most of these drugs (21 of 25) showed active uptake by plated human hepatocytes, with rifamycin SV (pan-transporter inhibitor) reducing the uptake by about 25%-95%. Metabolic turnover was estimated for 19 drugs after a few showed no measurable substrate depletion in liver microsomal incubations. IVIV extrapolation using in vitro data was evaluated to project human hepatic clearance of OAT2-alone substrates considering 1) uptake transport only, 2) metabolism only, and 3) transporter-enzyme interplay (extended clearance model). The transporter-enzyme interplay approach achieved improved prediction accuracy (average fold error = 1.9 and bias = 0.93) compared with the other two approaches. In conclusion, this study provides functional evidence for the role of OAT2-mediated hepatic uptake in determining the pharmacokinetics of several clinically important ECCS 1A drugs.