SINGLE-DOSE PHARMACOKINETICS AND ANTIBACTERIAL ACTIVITY OF DAPTOMYCIN, A NEW LIPOPEPTIDE ANTIBIOTIC, IN HEALTHY-VOLUNTEERS
SINGLE-DOSE PHARMACOKINETICS AND ANTIBACTERIAL ACTIVITY OF DAPTOMYCIN, A NEW LIPOPEPTIDE ANTIBIOTIC, IN HEALTHY-VOLUNTEERS
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DOI：
10.1128/aac.36.2.318
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发表时间：
1992-02-01
影响因子：
4.9
通讯作者：
BLACK, HR
中科院分区：
文献类型：
--
作者：
WOODWORTH, JR;NYHART, EH;BLACK, HR
进行了三个单独的单剂量研究，以确定达托霉素在健康志愿者中的配置和药代动力学。达托霉素以c -14标记的单剂量（1.0 mg/kg体重）和0.5至6.0 mg/kg之间的单剂量给药。所有剂量均为静脉注射。测定了2.0、3.0、4.0和6.0 mg/kg剂量对2株金黄色葡萄球菌（1株耐甲氧西林）和1株肠球菌的抑菌活性。给予C-14标记的达托霉素后，尿液和粪便中C-14的回收率占给药剂量的83%，其中尿液中C-14的回收率最高（78%）。尿和血浆中达托霉素的特异性分析表明，尿中存在代谢产物，但血浆中总C-14仅由达托霉素组成。剂量在0.5至6mg /kg之间呈线性，总体清除率有限（0.13至0.21 ml/min/kg），分布体积较小（0.10至0.15 l/ kg）。分布体积小可能是血浆蛋白结合高（90 ~ 95%）的一个因素。肾脏清除率占全身清除率的34 - 54%。达托霉素对所有三种试验菌株均表现出体内抗菌活性，其中对耐甲氧西林金黄色葡萄球菌的活性最大。预测三种菌株的MIC均约为13 μ g/ml，对应于总药物（结合加未结合）。根据药物的药代动力学和抗菌活性，预计4至6mg /kg/天的剂量，可能分次服用，是有效的。
Three separate single-dose studies were performed to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. Daptomycin was administered as a single C-14-labeled dose (1.0 mg/kg of body weight) and as single doses between 0.5 and 6.0 mg/kg. All doses were intravenous. Antibacterial activity was determined from doses of 2.0, 3.0, 4.0, and 6.0 mg/kg against two strains of Staphylococcus aureus (one methicillin resistant) and one Enterococcus strain. After administration of C-14-labeled daptomycin, recovery of C-14 in urine and feces accounted for 83% of the administered dose, with the greatest fraction (78%) appearing in the urine. Specific analysis for daptomycin in both urine and plasma indicated that metabolic products were present in urine, but total C-14 in plasma consisted of daptomycin only. Doses between 0.5 and 6 mg/kg were linear, with a limited total body clearance (0.13 to 0.21 ml/min/kg) and a small volume of distribution (0.10 to 0.15 liter/kg). The small volume of distribution may be a factor of the high plasma protein binding (90 to 95%). Renal clearance made up 34 to 54% of total body clearance. Daptomycin demonstrated in vivo antibacterial activity against all three test strains, with the greatest activity observed against methicillin-resistant S. aureus. The predicted MIC for all three strains was approximately 13-mu-g/ml, corresponding to total (bound plus unbound) drug. On the basis of the drug's pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective.