MacGowan Alasdair P
Bristol Centre for Antimicrobial Research and Evaluation, University of Bristol and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.
J Antimicrob Chemother. 2003 May;51 Suppl 2:ii17-25. doi: 10.1093/jac/dkg248.
The pharmacokinetics and pharmacodynamics of linezolid have been extensively investigated in laboratory models, healthy volunteers and patients. Three formulations exist: an intravenous (iv) form, film-coated tablets and an oral suspension. Linezolid can be assayed in serum and body fluids by HPLC and has good bioavailability with a Cmax at 0.5-2 h. The protein binding is 31%, and the volume of distribution is 30-50 L with adequate to good tissue penetration into skin blister fluids, bone, muscle, fat, alveolar cells, lung extracellular lining fluid and CSF. There are two major metabolites of linezolid (PNU-142586 and PNU-142300). Non-enzymic formation of PNU-142586 is the rate-limiting step in the clearance of linezolid, and linezolid and its two main metabolites plus several minor ones are all excreted in the urine. Dose linearity is evident in the Cmax and AUC across a wide range of doses. Gender and age have little effect on pharmacokinetics, but children have greater plasma clearance and volume of distribution and hence, have lower serum concentrations for equivalent doses in adults. No dose modification is needed in mild to moderate liver disease or any degree of renal impairment; however, both PNU-142586 and PNU-142300 accumulate in renal failure. Linezolid is bacteriostatic with a significant post-antibiotic effect against the key pathogens. In animal models of infection, the time the antibiotic concentration exceeds the MIC (t > MIC) helps to determine outcome, and a t > MIC of 40% is predictive of a bacteriostatic effect for both staphylococci and pneumococci. In man, t > MIC and AUC/MIC have been related to bacteriological and clinical outcomes. AUC and length of treatment are also related to the risk of thrombocytopenia.
利奈唑胺的药代动力学和药效学已在实验室模型、健康志愿者和患者中进行了广泛研究。现有三种剂型：静脉注射（iv）剂型、薄膜包衣片和口服混悬液。利奈唑胺可通过高效液相色谱法（HPLC）在血清和体液中进行测定，生物利用度良好，达峰时间（Cmax）为0.5 - 2小时。蛋白结合率为31%，分布容积为30 - 50升，对皮肤水疱液、骨骼、肌肉、脂肪、肺泡细胞、肺细胞外衬液和脑脊液有足够且良好的组织穿透力。利奈唑胺有两种主要代谢产物（PNU - 142586和PNU - 142300）。PNU - 142586的非酶促形成是利奈唑胺清除的限速步骤，利奈唑胺及其两种主要代谢产物加上几种次要代谢产物均经尿液排泄。在很宽的剂量范围内，Cmax和AUC呈现明显的剂量线性关系。性别和年龄对药代动力学影响较小，但儿童的血浆清除率和分布容积更大，因此，相同剂量下儿童的血清浓度低于成人。轻度至中度肝病或任何程度的肾功能损害均无需调整剂量；然而，PNU - 142586和PNU - 142300在肾衰竭时会蓄积。利奈唑胺具有抑菌作用，对关键病原体有显著的抗生素后效应。在感染动物模型中，抗生素浓度超过最低抑菌浓度的时间（t > MIC）有助于确定治疗结果，对于葡萄球菌和肺炎球菌，t > MIC为40%可预测抑菌效果。在人体中，t > MIC和AUC/MIC与细菌学和临床结果相关。AUC和治疗时长也与血小板减少症的风险相关。
