PHARMACOKINETICS AND TOLERANCE OF DU-6859A, A NEW FLUOROQUINOLONE, AFTER SINGLE AND MULTIPLE ORAL DOSES IN HEALTHY-VOLUNTEERS
PHARMACOKINETICS AND TOLERANCE OF DU-6859A, A NEW FLUOROQUINOLONE, AFTER SINGLE AND MULTIPLE ORAL DOSES IN HEALTHY-VOLUNTEERS
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DOI：
10.1128/aac.39.1.170
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发表时间：
1995-01-01
影响因子：
4.9
通讯作者：
TANAKA, M
中科院分区：
文献类型：
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作者：
NAKASHIMA, M;UEMATSU, T;TANAKA, M
在日本健康男性志愿者中研究了DU-6859 a（7-[（7S）-7-氨基-5-氮杂螺[2，4]庚烷-5-基]-8-氯-6-氟-1- [（1 R，2S）-2-氟-1-环丙基]-1，4-二氢-4-氧代-3-喹啉羧酸倍半水合物）单次给药后的药代动力学和耐受性（25、50、100和200 mg）和多次（100 mg，每日三次，持续6天，第7天每日一次，50 mg，每12 h一次，持续13次）口服给药。DU-6859 a在碱剂量下耐受良好，所有36例受试者均完成了研究;在多次给药（100 mg，每日三次）研究中，5名志愿者出现轻度一过性软便，1名志愿者出现轻度一过性腹泻，这是报告的唯一副作用。200 mg单次给药和100 mg每日3次给药方案后，尿液中未观察到药物晶体。DU-6859 a在空腹状态下吸收迅速。对于25- 200 mg剂量，血清中的平均最大浓度（C-max）范围为0.29 - 1.86 μ g/ml，达到C-max的平均时间范围为1.0 - 1.3 h。终末半衰期范围为4.4 - 5.0 h。曲线下面积呈剂量依赖性增加。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/kg，表明组织渗透性良好。在18小时内，原型药物的累积尿液回收率为给药剂量的69 - 74%，而200 mg剂量给药后48小时的粪便排泄量约占给药剂量的69%-74%。剂量的3%。摄食量对DU-6859 a的吸收速率和程度没有临床显著影响。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，这表明几乎没有药物蓄积。
The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro-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 alkl 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 (C-max) ranged from 0.29 to 1.86 mu g/ml for the 25- to 200-mg dose, and the mean time to reach C-max 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 18 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 extent 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.