机械基础Cabotegravir-Glucuronide性格的人类。

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帕特尔M, Eberl HC,狼,皮埃尔•E Polli JW, Zamek-Gliszczynski乔丹

机械基础Cabotegravir-Glucuronide性格的人类。

J Exp其他杂志》2019年8月,370 (2):269 - 277。doi: 10.1124 / jpet.119.258384。Epub 2019年6月7日。

PubMed ID

31175220 (在PubMed

]

文摘

Cabotegravir,正在开发一种新的整合酶抑制剂治疗和预防艾滋病毒,主要是由UDP-glucuronosyltransferase代谢(UGT) 1 a1和UGT1A9直接醚葡糖苷酸代谢物。这些研究的目的是阐明人类cabotegravir-glucuronide性格的机械基础。Cabotegravir glucuronidation主要是肝(> 95%)以最少的肠道和肾脏的贡献。鼠肝脏灌注证明cabotegravir-glucuronide形成在肝脏进行类似的胆汁和正弦排泄,符合高浓度的葡糖苷酸在人体胆汁和尿液。Cabotegravir-glucuronide胆汁排泄是由多种resistance-associated蛋白(MRP) 2(不是经由乳腺癌抗蛋白质或22),而基底肝脏排泄到正弦血液是通过MRP3(分数运输(英尺)= 0.81)和MRP4(英尺= 0.19)。令人惊讶的是,尽管高尿恢复hepatically-formed cabotegravir-glucuronide,流通中的代谢物水平都可以忽略不计,这一现象符合快速代谢物间隙。Cabotegravir-glucuronide被肝脏吸收转运蛋白运输有机anion-transporting (OAT)多肽(OATP) 1 b1和OATP1B3;然而,代谢物间隙由循环肝摄取低肝血流量(2.7%)和无法解释的最小的系统性风险。相反,循环cabotegravir-glucuronide经历有效肾清除率,吸收到近端小管是由OAT3(不是经由OAT1),和随后的分泌到尿液MRP2(英尺= 0.66)和MRP4(英尺= 0.34)。这些研究提供机械的见解cabotegravir-glucuronide的性格,与明显的尿hepatically-formed代谢物复苏和最小的系统性风险,包括冗余的转运蛋白的部分贡献任何给定的过程基于定量蛋白质组学。 SIGNIFICANCE STATEMENT: The role of membrane transporters in metabolite disposition, especially glucuronides, and as sites of unexpected drug-drug interactions, which alter drug efficacy and safety, has been established. Cabotegravir-glucuronide, formed predominantly by direct glucuronidation of parent drug in liver, was the major metabolite recovered in human urine (27% of oral dose) but was surprisingly not detected in systemic circulation. To our knowledge, this is the first mechanistic description of this phenomenon for a major hepatically-formed metabolite to be excreted in the urine to a large extent, but not circulate at detectable levels. The present study elucidates the mechanistic basis of cabotegravir-glucuronide disposition in humans. Specific hepatic and renal transporters involved in the disposition of cabotegravir-glucuronide, with their fractional contribution, have been provided.

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药物

Cabotegravir