通过尿酸重吸收转运蛋白 1 的反式抑制增强 Dotinurad 的促尿酸排泄作用,Drug Metabolism and Disposition

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通过尿酸重吸收转运蛋白 1 的反式抑制增强 Dotinurad 的促尿酸排泄作用
Drug Metabolism and Disposition ( IF 4.4 ) Pub Date : 2023-11-01 , DOI: 10.1124/dmd.123.001412
Kazuki Fujita ₁ , Qiunan Zhu ₁ , Hiroshi Arakawa ₁ , Yoshiyuki Shirasaka ₁ , Ikumi Tamai ₂

Affiliation

尿酸盐转运蛋白 1 (URAT1) 是负责肾近曲小管尿酸 (UA) 重吸收的转运蛋白，也是促尿酸排泄药物的药理学靶点。丙磺舒和苯溴马隆已被用作促尿酸排泄药，而 dotinurad 最近在日本获得批准。值得注意的是，dotinurad 对 URAT1 的体外IC ₅₀不足以解释其根据临床未结合血浆浓度估计的体内促尿酸排泄效应，这表明除了与 URAT1 胞外域的 UA 摄取竞争之外，还存在其他机制（顺式-抑制）。在本研究中，反式抑制被假设为dotinurad抑制URAT1的机制，其中细胞内积累的dotinurad使URAT1失活。在表达 URAT1 的 Madin-Darby 犬肾 II 细胞和非洲爪蟾卵母细胞中，与 dotinurad 预孵育比单独共孵育更能增强抑制作用，但用苯溴马隆或丙磺舒未观察到这种作用。在共同孵育下，dotinurad 以竞争性方式抑制 UA 摄取（顺式抑制）。当我们将 dotinurad 直接预先注射到卵母细胞中并立即测量 [ ¹⁴ C]UA 摄取而无需共孵育（仅反式抑制）时，dotinurad 非竞争性抑制 UA 摄取。URAT1 是 UA 和烟酸 (NA) 等单羧酸盐的交换转运蛋白。预注射的 dotinurad 和细胞外 UA 分别减弱和促进 [ ³ H]NA 的流出，而预注射苯溴马隆或丙磺舒则不影响它，这表明 dotinurad通过减弱 URAT1 介导的单羧酸流出而表现出反式抑制，这是 URAT1 吸收 UA 的驱动力。因此，dotinurad 通过顺式和反式抑制改善 URAT1 介导的 UA 重吸收，这解释了其临床上比体外IC ₅₀值估计的更强的促尿酸排泄作用。

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Potentiation of the Uricosuric Effect of Dotinurad byTrans-Inhibition of the Uric Acid Reabsorptive Transporter 1

Urate transporter 1 (URAT1) is a transporter responsible for uric acid (UA) reabsorption by renal proximal tubules and a pharmacological target of uricosuric agents. Probenecid and benzbromarone have been used as uricosuric agents, while dotinurad was recently approved in Japan. Notably, the in vitro IC₅₀ of dotinurad on URAT1 is not strong enough to explain its in vivo uricosuric effect estimated based on clinical unbound plasma concentrations, suggesting the presence of mechanisms other than competition with UA uptake at the extracellular domain of URAT1 (cis-inhibition). In this study, trans-inhibition was hypothesized as the mechanism underlying URAT1 inhibition by dotinurad, wherein intracellularly accumulated dotinurad inactivates URAT1. In URAT1-expressing Madin–Darby Canine Kidney-II cells and Xenopus oocytes, pre-incubation with dotinurad potentiated the inhibitory effect more than co-incubation alone, but this effect was not observed with benzbromarone or probenecid. Under co-incubation, dotinurad inhibited UA uptake in a competitive manner (cis-inhibition). When we pre-injected dotinurad directly into oocytes and immediately measured [¹⁴C]UA uptake without coincubation (only trans-inhibition), dotinurad noncompetitively inhibited UA uptake. URAT1 is an exchange transporter for UA and monocarboxylates such as nicotinic acid (NA). Pre-injected dotinurad and extracellular UA attenuated and facilitated efflux of [³H]NA, respectively, whereas pre-injection of benzbromarone or probenecid did not affect it, suggesting that dotinurad exhibits trans-inhibition by attenuating URAT1-mediated efflux of monocarboxylates, which is a driving force for UA uptake by URAT1. Accordingly, dotinurad ameliorates URAT1-mediated UA reabsorption by both cis- and trans-inhibition, explaining its clinically stronger uricosuric effect than that estimated by the in vitro IC₅₀ value.

更新日期：2023-10-12

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