Nakashima M, Uematsu T, Kosuge K, Umemura K, Hakusui H, Tanaka M
Department of Pharmacology, Hamamatsu University School of Medicine, Shizuoka, Japan.
Antimicrob Agents Chemother. 1995 Jan;39(1):170-4. doi: 10.1128/AAC.39.1.170.
The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation.
对DU-6859a（7-[(7S)-7-氨基-5-氮杂螺[2,4]庚烷-5-基]-8-氯-6-氟-1-[(1R,2S)-2-氟-1-环丙基]-1,4-二氢-4-氧代-3-喹啉羧酸倍半水合物）在健康日本男性志愿者单次（25、50、100和200毫克）和多次（每天3次，每次100毫克，共6天，第7天每天1次，以及每12小时50毫克，共13剂）口服给药后的药代动力学和耐受性进行了研究。所有剂量的DU-6859a耐受性良好，36名受试者均完成了研究；在多剂量（每天3次，每次100毫克）研究中，5名志愿者出现轻度短暂软便，1名志愿者出现轻度短暂腹泻，这是报告的仅有的副作用。单次200毫克剂量和每天3次、每次100毫克给药方案后，尿液中未观察到药物结晶。DU-6859a在禁食状态下迅速吸收。25至200毫克剂量时，血清中的平均最大浓度（Cmax）范围为0.29至1.86微克/毫升，达到Cmax的平均时间范围为1.0至1.3小时。终末半衰期范围为4.4至5.0小时。曲线下面积呈剂量依赖性增加。该药物的血清蛋白结合率约为50%。表观分布容积明显超过1升/千克，表明组织穿透力良好。在48小时内，未变化药物的累积尿回收率相当于给药剂量的69%至-74%，而200毫克剂量后48小时内的粪便排泄量约占剂量的3%。食物摄入对DU-6859a吸收的速率和程度没有在临床上显著的影响。在多次口服给药期间，药物在血清中的蓄积接近理论预测值，这表明实际上没有药物蓄积。
