Dan T, Koga H
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Eur J Pharmacol. 1990 Oct 23;187(3):303-12. doi: 10.1016/0014-2999(90)90357-c.
It has been proposed that a urate-anion exchanger system in brush border membrane vesicles (BBMV), which mediates hydroxyl ion (OH-) gradient-dependent urate uptake, is the most likely route for the mediation of urate transport in the first step of urate reabsorption in the proximal tubules. Luminal drugs which inhibit urate reabsorption would inhibit the transport of urate into the cell by blocking the urate-anion exchanger. To confirm this hypothesis, we investigated the inhibitory effects of well-known uricosuric drugs on the OH-/urate exchange in BBMV. The rank order of potency was benzbromarone greater than tienilic acid greater than sulfinpyrazone greater than probenecid, which is consistent with clinical doses in man. AA-193 (5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carb oxylic acid), an excellent candidate for a uricosuric, exerted the most potent inhibition on urate uptake (Ki = 0.12 microM). In contrast with that by stilbene disulfonates, the inhibition by AA-193 or benzbromarone was reversible.
有人提出，刷状缘膜囊泡（BBMV）中的尿酸盐 - 阴离子交换系统介导依赖于羟离子（OH-）梯度的尿酸盐摄取，这是近端小管中尿酸盐重吸收第一步中尿酸盐转运介导的最可能途径。抑制尿酸盐重吸收的管腔药物会通过阻断尿酸盐 - 阴离子交换器来抑制尿酸盐进入细胞。为了证实这一假设，我们研究了著名的促尿酸排泄药物对BBMV中OH-/尿酸盐交换的抑制作用。效力顺序为苯溴马隆大于替尼酸大于磺吡酮大于丙磺舒，这与人体临床剂量一致。AA - 193（5 - 氯 - 7,8 - 二氢 - 3 - 苯基呋喃并[2,3 - g] - 1,2 - 苯并异恶唑 - 7 - 羧酸）是一种优秀的促尿酸排泄药物候选物，对尿酸盐摄取具有最有效的抑制作用（Ki = 0.12 microM）。与二苯乙烯二磺酸盐不同，AA - 193或苯溴马隆的抑制作用是可逆的。
