Kanamaru M, Uematsu T, Nagashima S, Mizuno A, Terakawa M, Sugiyama A, Nakashima M
Department of Pharmacology, Hamamatsu University School of Medicine, Osaka, Japan.
J Clin Pharmacol. 1993 Nov;33(11):1122-31. doi: 10.1002/j.1552-4604.1993.tb01950.x.
The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosuric activities of FK366 were studied in healthy volunteers given a single oral dose of 150, 300, or 600 mg after fasting, 600 mg after a meal, or 300 mg twice a day for 8 days after meals. The AR inhibition was assessed by the percent reduction from the predrug dulcitol values in red blood cells converted from exogenous galactose by AR. Aldose reductase inhibition paralleled the plasma concentrations of FK366, with maximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and 600 mg, respectively. With multiple dosing, the inhibition scarcely differed between the first (41.8%) and last doses (41.5%). Serum uric acid decreased dose dependently, with a minimum concentration of 4.0 mg/dL (predrug: 5.5 mg/dL) 8 hours after receiving 600 mg. With multiple dosing, serum uric acid levels declined rapidly and remained at a concentration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric acid was high on day 1 (879 mg/day), but decreased significantly to 654 mg/day on day 2 and then stabilized. The pharmacokinetics of FK366 were linear over the dose range studied, with an elimination half-life of 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was well tolerated by all subjects.
在健康志愿者中开展了FK366的药代动力学研究，以及其醛糖还原酶（AR）抑制活性和促尿酸排泄活性研究。志愿者分别在空腹状态下单次口服150、300或600 mg，餐后单次口服600 mg，或餐后每天两次、每次300 mg给药8天。通过计算AR将外源性半乳糖转化生成的红细胞中半乳糖醇的前药值降低的百分比来评估AR抑制作用。醛糖还原酶抑制作用与FK366的血浆浓度平行，在150、300和600 mg剂量下，最大抑制率分别为31.6%、48.0%和56.9%。多次给药时，首次给药（41.8%）和末次给药（41.5%）时的抑制作用几乎没有差异。血清尿酸浓度呈剂量依赖性降低，在服用600 mg后8小时达到最低浓度4.0 mg/dL（前药浓度：5.5 mg/dL）。多次给药时，血清尿酸水平迅速下降，从第3天开始维持在3.1 mg/dL的浓度。尿酸的尿排泄量在第1天较高（879 mg/天），但在第2天显著下降至654 mg/天，随后趋于稳定。在所研究的剂量范围内，FK366的药代动力学呈线性，消除半衰期为8.2小时，以原形药物形式经尿液回收的比例为27.2%。所有受试者对FK366的耐受性良好。
