Horie S, Nagai H, Yuuki T, Narita Y, Tsuda Y, Nakajima T, Nakamura N
Pharmacology Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan.
J Diabetes Complications. 1998 May-Jun;12(3):163-9. doi: 10.1016/s1056-8727(97)00108-6.
To investigate the effect of SG-210, a potent inhibitor selective to aldose reductase (ARI), on the impaired polyol pathway, we examined biochemically and histologically the potencies of this compound in streptozotocin-induced diabetic or galactosemic rats. The study with diabetic rats showed that SG-210 (1-10 mg x kg(-1)) dose-dependently inhibited sorbitol accumulations in erythrocytes, sciatic nerves, lens, and retina with ED50 values of 1.4, 1.3, 3.5, and 4.6 mg x kg(-1), respectively. Zenarestat, currently under clinical trials both in Japan and the United States, was about two or over five times less potent than SG-210 in suppressing sorbitol contents of erythrocytes or other tissues, respectively. Epalrestat, commercially available, was much less potent in reducing the contents with ED50 values of more than 30 mg x kg(-1) in all of the cells and the tissues examined. An extensive study using galactosemic rats indicated that SG-210 (3-30 mg x kg(-1)) inhibited galactitol accumulations in lens and retina as well as in erythrocytes, preventing the progression of histological abnormalities in lens accompanied by the reduction in galactitol contents. Epalrestat (3-30 mg x kg(-1)) failed to show any significant effects. Pharmacokinetic studies suggested that SG-210 has a high bioavailability and possesses a long half-life in rats (ca. 10 h). Taken together with its excellent pharmacokinetic profiles, the potent suppressive effects of SG-210 observed in this study may be available as a new treatment of diabetic complications.
为研究强效醛糖还原酶选择性抑制剂（ARI）SG - 210对受损多元醇途径的影响，我们对链脲佐菌素诱导的糖尿病大鼠或半乳糖血症大鼠进行了生化和组织学研究，以检测该化合物的效能。对糖尿病大鼠的研究表明，SG - 210（1 - 10 mg·kg⁻¹）能剂量依赖性地抑制红细胞、坐骨神经、晶状体和视网膜中山梨醇的积累，其半数有效剂量（ED50）值分别为1.4、1.3、3.5和4.6 mg·kg⁻¹。目前正在日本和美国进行临床试验的泽那司他，在抑制红细胞或其他组织中山梨醇含量方面，效力分别比SG - 210低约两倍或五倍以上。市售的依帕司他在降低所有检测细胞和组织中的含量方面效力低得多，其ED50值超过30 mg·kg⁻¹。使用半乳糖血症大鼠的广泛研究表明，SG - 210（3 - 30 mg·kg⁻¹）能抑制晶状体、视网膜以及红细胞中半乳糖醇的积累，防止晶状体组织学异常的进展，并伴有半乳糖醇含量的降低。依帕司他（3 - 30 mg·kg⁻¹）未显示出任何显著效果。药代动力学研究表明，SG - 210具有高生物利用度，在大鼠体内具有较长的半衰期（约10小时）。结合其优异的药代动力学特征，本研究中观察到的SG - 210的强效抑制作用可能成为糖尿病并发症的一种新治疗方法。
