PHARMACOKINETICS AND SAFETY OF NM441, A NEW QUINOLONE, IN HEALTHY MALE-VOLUNTEERS
PHARMACOKINETICS AND SAFETY OF NM441, A NEW QUINOLONE, IN HEALTHY MALE-VOLUNTEERS
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DOI：
10.1002/j.1552-4604.1994.tb04007.x
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发表时间：
1994-09-01
影响因子：
2.9
通讯作者：
TAKEBE, Y
中科院分区：
文献类型：
--
作者：
NAKASHIMA, M;UEMATSU, T;TAKEBE, Y
NM441 是一种新的噻嗪酮喹啉羧酸衍生物 NM394 的前药，其安全性和药代动力学在健康男性志愿者中进行了评估，该志愿者口服单剂量 20、50、100、200 和 300 mg，以及多次剂量 300 mg，每天两次，持续 6.5 天。症状、体格检查、实验室检查、心电图（ECG）、脑电图（EEG）或平衡试验均未观察到明显异常。活性代谢物NM394的平均血浆浓度在0.5至1.0小时之间达到峰值，并且在剂量为100、200和400mg时最大浓度分别为0.68、1.09和1.88μg/mL。平均半衰期为7.7至8.9小时，且不受剂量影响。 48小时内NM394的平均尿排泄率分别为剂量的46.0%、38.3%和30.6%，其他代谢物以剂量的7%从尿中排出。 NM394 的平均唾液浓度约为血浆浓度的 20%。服用400 mg后72小时内，NM394和NM441的平均粪便排泄率分别为52.9%和4.2%。 C-max、AUC 和尿排泄率不会因食物摄入而改变，而 T-max 略有延长。在多剂量研究中，NM394的血浆浓度在第3天或第4天达到稳态，此后没有发生进一步的积累。多次给药期间和给药后48小时，NM394的平均尿排泄率为49.0%。 NM441 可接受的安全性和耐受性以及明确的药代动力学特征支持进一步的测试。
The safety and pharmacokinetics of NM441, a prodrug of a new thiazeto-quinoline carboxylic acid derivative, NM394, were evaluated in healthy male volunteers given the drug orally in single doses of 20, 50, 100, 200, and 300 mg, and multiple doses of 300 mg twice daily for 6.5 days. No remarkable abnormalities were observed in symptoms, physical tests, laboratory tests, electrocardiogram (ECG), electroencephalogram (EEG), or equilibrium test. The mean plasma concentrations of active metabolite NM394 peaked between 0.5 and 1.0 hours, and the maximum concentrations were 0.68, 1.09, and 1.88 mu g/mL at doses of 100, 200, and 400 mg, respectively. The mean half-lives were 7.7 to 8.9 hours and were not affected by dose. The mean urinary excretion rates of NM394 were 46.0, 38.3, and 30.6% of the doses within 48 hours, respectively, and other metabolites were excreted in urine by 7% of the doses. The mean salivary concentrations of NM394 were approximately 20% of the plasma concentrations. The mean fecal excretion rates of NM394 and NM441 were 52.9 and 4.2%, respectively within 72 hours after dosing of 400 mg. The C-max, AUC, and urinary excretion rates were not altered by food intake, whereas the T-max was prolonged slightly. In the multiple-dose study, the steady state of plasma concentration of NM394 was achieved on day 3 or 4, and further accumulation did not occur thereafter. The mean urinary excretion rate of NM394 was 49.0% during and 48 hours after the multiple administration. The acceptable safety and tolerance and defined pharmacokinetic characteristics of NM441 support further testing.