Kikuchi M
Department of Endocrinology and Metabolism, Asahi Life Foundation, Tokyo, Japan.
Diabet Med. 1996 Sep;13(9 Suppl 6):S151-5.
Two novel oral hypoglycaemic agents, NN623 and A4166, have been developed and are now in phase II clinical trial. Both agents have several common characteristics from sulphonylureas. NN623 is a stereoisomer of derivatives of benzoic acid and A4166 is also a stereoisomer of phenylalanine derivative. The predominant mechanism of the action is thought to be like sulphonylureas. Both NN623 and A4166 occupy, at least partly, a common receptor site with glibenclamide and close the ATP-dependent K+ channel. They are rapidly absorbed from the intestine and are eliminated mainly into the bile. NN623 is about 10 times more potent in hypoglycaemic action than glibenclamide and 100 times more than A4166 in terms of dosage. When 1.0 mg NN623 or 60 mg A4166 was given orally in the post-absorptive state to healthy volunteers, both agents evoked hypoglycaemia by 40 min. The duration of hypoglycaemia after NN623 was longer than after A4166 by about 1 hour. The effect of food on their bioavailability is similar. Food has marked influence on the absorption of both drugs and on their efficacy. When 1 mg of NN623 or 60 mg of A4166 was administered just before the meal, Tmax of NN623 and A4166 was 34 +/- 18 min and 18 +/- 6 min, while T1/2 was 0.64 +/- 0.12 h and 0.98 +/- 0.06 h, respectively. The postprandial rise in plasma glucose was reduced at 45 min and thereafter over 4-h after 1.0 mg NN623 and at 30 min to 90 min after 60 mg A4166. Plasma insulin levels rose more than those after placebo from 30 to 90 min after NN623 and at 20 to 40 min after A4166. Both agents stimulated insulin release much more in the postprandial than in the fasting state. There was no difference in the bioavailability after 5 or 7 days of administration. However, when administered immediately after the meal, the absorption of both drugs was delayed and the rise in plasma absorption was not suppressed until 60 min after the meal. Both fasting and postprandial hyperglycaemia were reduced after 1 to 4 weeks of premeal treatment with 0.5 mg NN623 or 60 mg A4166 in subjects with NIDDM. Plasma glucose levels were decreased over 4 h after NN623 and over 1 h after A4166. The meal-induced insulin response was almost doubled by NN623 over 2 h and 1 h by A4166. There was no difference in the bioavailability after breakfast between the first and last administrations of both drugs. In conclusion, a rapid rise in plasma insulin levels is associated with the suppression of postprandial hyperglycaemia.
两种新型口服降糖药NN623和A4166已研发出来，目前正处于II期临床试验阶段。这两种药物与磺脲类药物有几个共同特征。NN623是苯甲酸衍生物的立体异构体，A4166也是苯丙氨酸衍生物的立体异构体。其主要作用机制被认为与磺脲类药物相似。NN623和A4166至少部分地与格列本脲占据共同的受体位点，并关闭ATP依赖性钾通道。它们在肠道吸收迅速，主要经胆汁排泄。就降血糖作用而言，NN623的效力约为格列本脲的10倍，按剂量计算比A4166强100倍。在吸收后状态下，给健康志愿者口服1.0毫克NN623或60毫克A4166，两种药物在40分钟内均引起低血糖。NN623引起的低血糖持续时间比A4166长约1小时。食物对它们生物利用度的影响相似。食物对两种药物的吸收及其疗效均有显著影响。在餐前服用1毫克NN623或60毫克A4166时，NN623和A4166的达峰时间（Tmax）分别为34±18分钟和18±6分钟，而半衰期（T1/2）分别为0.64±0.12小时和0.98±0.06小时。在服用1.0毫克NN623后45分钟及之后的4小时内，以及服用60毫克A4166后30分钟至90分钟内，餐后血糖升高幅度降低。服用NN623后30至90分钟以及服用A4166后20至40分钟，血浆胰岛素水平比服用安慰剂后升高得更多。两种药物在餐后比空腹状态下更能刺激胰岛素释放。给药5天或7天后生物利用度无差异。然而，在餐后立即给药时，两种药物的吸收均延迟，血浆吸收升高直到餐后60分钟才受到抑制。对非胰岛素依赖型糖尿病（NIDDM）患者进行餐前0.5毫克NN623或60毫克A4166治疗1至4周后，空腹和餐后高血糖均降低。服用NN623后4小时内及服用A4166后1小时内血浆葡萄糖水平下降。NN623使餐后胰岛素反应在2小时内几乎翻倍，A4166在1小时内使其翻倍。两种药物首次和末次早餐给药后的生物利用度无差异。总之，血浆胰岛素水平的快速升高与餐后高血糖的抑制有关。
