Gontijo Aline Vidal Lacerda, Grégoire Nicolas, Lamarche Isabelle, Gobin Patrice, Couet William, Marchand Sandrine
Inserm U1070, Pôle Biologie Santé, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
Inserm U1070, Pôle Biologie Santé, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France.
Antimicrob Agents Chemother. 2014 Jul;58(7):3950-6. doi: 10.1128/AAC.02819-14. Epub 2014 May 5.
The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (VELF), a passive diffusion clearance (QELF) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg(-1)). The km was estimated to be 133 μg ml(-1), and the Vmax, in-to-Km ratio was equal to 2.5 × 10(-3) liter h(-1) kg(-1), which was 37 times higher than the QELF (6.7 × 10(-5) liter h(-1) kg(-1)). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.
本研究的目的是调查大鼠肺内给予硫酸多粘菌素后多粘菌素的药代动力学特性。以0.35mg/kg体重的剂量给大鼠输注或雾化给予多粘菌素，给药后4小时测量血浆药物浓度。在静脉注射和雾化给药后0.5、2和4小时也进行支气管肺泡灌洗（BAL），以估计上皮衬液（ELF）中的药物浓度。静脉输注和雾化吸入给药后，分布平衡时（给药后2小时）的非结合多粘菌素血浆浓度几乎相同。静脉给药后，BAL样本中未检测到ELF药物浓度，但雾化给药后2小时和4小时，ELF药物浓度比非结合血浆药物水平高约1800倍。采用一个模型对血浆和ELF药物浓度进行同步药代动力学建模，该模型的特征为ELF的固定生理体积（VELF）、血浆与ELF之间的被动扩散清除率（QELF）以及从ELF到中央室的非线性流入转运，通过将多粘菌素雾化剂量降低10倍（0.035mg kg-1）来评估该模型。估计Km为133μg ml-1，Vmax与Km之比等于2.5×10-3升 h-1 kg-1，比QELF（6.7×10-5升 h-1 kg-1）高37倍。本研究表明，雾化气溶胶给药后ELF药物浓度高于静脉给药，对于多粘菌素等低渗透性抗生素，雾化给药在治疗肺部感染方面比静脉给药具有更大的潜力。
