低氧高碳酸环境对大鼠肺炎模型中左氧氟沙星分布的影响
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摘要
目的探讨低氧高碳酸血症下左氧氟沙星(LVFX)在大鼠肺炎模型中的分布及浓度变化。方法选取大肠埃希菌菌悬液注入大鼠气管,建立低氧高碳酸血症肺炎大鼠模型及单纯肺炎大鼠模型;建模成功后,按50 mg/kg静脉注射左氧氟沙星;分别于给药后0. 5,1,2,4,8,12,24 h时采集血浆、支气管肺组织、支气管肺泡灌洗液(BALF),采用高效液相色谱法测定样本中左氧氟沙星药物浓度。采用Kinetica 4. 4软件计算药代动力学参数。结果给药后,各组血浆、支气管肺组织和BALF药-时曲线均符合二室模型。单纯肺炎大鼠模型血浆、支气管肺组织及BALF中清除率分别为(1. 07±0. 33) mg/(kg·h),(1. 31±0. 14) mg/(kg·h)及(1. 18±0. 09) mg/(kg·h),0～24 h药-时曲线下面积(AUC_(0-24))分别为(21. 05±4. 36) mg·h/L,(40. 83±7. 49) mg·h/kg及(1. 34±0. 12) mg·h/L;低氧高碳酸血症大鼠肺炎模型血浆、支气管肺组织及BALF中清除率分别为(1. 23±0. 18) mg/(kg·h),(1. 97±0. 22) mg/(kg·h)及(1. 83±0. 26) mg/(kg·h),AUC_(0-24)分别为(14. 94±3. 15) mg·h/L,(26. 01±4. 73) mg·h/kg,(0. 93±0. 13) mg·h/L。结论低氧高碳酸环境下,左氧氟沙星在肺炎模型大鼠中支气管肺组织和BALF中的分布浓度明显降低,同时清除率增加。慢性呼吸衰竭合并肺炎的治疗中,需积极纠正低氧高碳酸血症状态,以增加药物吸收,达到药物最佳利用目的。
Objective To investigate the distribution and concentration changes of levofloxacin in the pneumonia rat model with hypoxia and hypercapnia. Methods Escherichia coli suspension was injected into rat trachea to establish hypoxic and hypercapnia pneumonia rat model and simple pneumonia rat model. After successful modeling,levofloxacin was injected intravenously at a dose of 50 mg/kg,and then the plasma,bronchial lung tissues and bronchoalveolar lavage fluid( BALF) were collected at 0. 5,1,2,4,8,12,24 h after injecting levofloxacin. The concentration of levofloxacin was detected by high performance liquid chromatography( HPLC). The pharmacokinetic parameters were calculated by using Kinetica 4. 4 software. Results After giving drugs,the drug-time curves of plasma and bronchial lung tissue and BALF in each group conformed to the two-compartment model. In simple pneumonia group, the clearance in plasma,bronchial lung tissues and BALF were( 1. 07 ± 0. 33) mg/( kg·h),(1. 31 ± 0. 14) mg/( kg·h) and(1. 18 ± 0. 09) mg/( kg·h),respectively,the 0-24 h area under concentration-time curves( AUC)_(0-24) were( 21. 05 ± 4. 36) mg· h/L,( 40. 83 ± 7. 49) mg· h/kg and( 1. 34 ± 0. 12) mg · h/L, respectively. In hypoxia and rcapnia pneumonia group, the clearance in plasma, bronchial lung tissues and BALF were( 1. 23 ± 0. 18) mg/(kg· h),(1. 97 ± 0. 22) mg/(kg· h) and(1. 83 ± 0. 26) mg/(kg· h),respectively, AUC_(0-24) were(14. 94 ±3. 15) mg·h/L,( 26. 01 ± 4. 73) mg · h/kg and( 0. 93 ± 0. 13) mg · h/L, respectively. Conclusion In the hypoxia and hypercapnia environment, the concentration of levofloxacin in the bronchial lung tissue and BALF in the pneumonia rats were significantly reduced,the clearance rate was increased. In the treatment of chronic respiratory failure complicated with pneumonia,attention should be paid to actively correct hypoxia and hypercapnia in order to increase drug absorption and achieve the goal of optimum drug utilization.
Objective To investigate the distribution and concentration changes of levofloxacin in the pneumonia rat model with hypoxia and hypercapnia. Methods Escherichia coli suspension was injected into rat trachea to establish hypoxic and hypercapnia pneumonia rat model and simple pneumonia rat model. After successful modeling,levofloxacin was injected intravenously at a dose of 50 mg/kg,and then the plasma,bronchial lung tissues and bronchoalveolar lavage fluid( BALF) were collected at 0. 5,1,2,4,8,12,24 h after injecting levofloxacin. The concentration of levofloxacin was detected by high performance liquid chromatography( HPLC). The pharmacokinetic parameters were calculated by using Kinetica 4. 4 software. Results After giving drugs,the drug-time curves of plasma and bronchial lung tissue and BALF in each group conformed to the two-compartment model. In simple pneumonia group, the clearance in plasma,bronchial lung tissues and BALF were( 1. 07 ± 0. 33) mg/( kg·h),(1. 31 ± 0. 14) mg/( kg·h) and(1. 18 ± 0. 09) mg/( kg·h),respectively,the 0-24 h area under concentration-time curves( AUC)_(0-24) were( 21. 05 ± 4. 36) mg· h/L,( 40. 83 ± 7. 49) mg· h/kg and( 1. 34 ± 0. 12) mg · h/L, respectively. In hypoxia and rcapnia pneumonia group, the clearance in plasma, bronchial lung tissues and BALF were( 1. 23 ± 0. 18) mg/(kg· h),(1. 97 ± 0. 22) mg/(kg· h) and(1. 83 ± 0. 26) mg/(kg· h),respectively, AUC_(0-24) were(14. 94 ±3. 15) mg·h/L,( 26. 01 ± 4. 73) mg · h/kg and( 0. 93 ± 0. 13) mg · h/L, respectively. Conclusion In the hypoxia and hypercapnia environment, the concentration of levofloxacin in the bronchial lung tissue and BALF in the pneumonia rats were significantly reduced,the clearance rate was increased. In the treatment of chronic respiratory failure complicated with pneumonia,attention should be paid to actively correct hypoxia and hypercapnia in order to increase drug absorption and achieve the goal of optimum drug utilization.
引文
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[9]DEVANEY J,CURLEY GF,HAYES M,et al.Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia[J].Crit Care,2013,17(2):R82.
[10]OLSEN KM,GENTRY-NIELSEN M,YUE YM,et al.Effect of Ethanol on Fluoroquinolone Efficacy in a Rat Model of Pneumococcal Pneumonia[J].Antimicrob Agents Chemother,2006,50(1):210-219.
[11]CONTE JJ,GOLDEN JA,MCIVER M.Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects[J].Int J Antimicrob Agents,2006,28(2):114-121.
[12]TUNITSKAYA VL,KHOMUTOV AR,KOCHETKOV SN,et al.Inhibition of DNA Gyrase by Levofloxacin and Related Fluorine-Containing Heterocyclic Compounds[J].Acta Naturae,2011,3(4):94-99.
[13]AHMAD I,BANO R,SHERAZ MA.Photodegradation of levofloxacin in aqueous and organic solvents:a kinetic study[J].Acta Pharm,2013,63(2):223-229.
[14]XU K,BEN W,LING W,et al.Impact of humic acid on the degradation of levofloxacin by aqueous permanganate:Kinetics and mechanism[J].Water Res,2017,123:67-74.
[15]PEA F,DI QUAL E,CUSENZA A,et al.Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia[J].Clin Pharmacokinet,2003,42(6):589-598.
[2]PHILLIPS-HOULBRACQ M,RICARD JD,FOUCRIER A,et al.Pathophysiology of Escherichia coli pneumonia:Respective contribution of pathogenicity islands to virulence[J].Int J Med Microbiol,2018,S1438-4221(17):30502-30507.
[3]NAKAI H,SATO T,UNO T,et al.Mutant selection window of four quinolone antibiotics against clinical isolates of Streptococcus pneumoniae,Haemophilus influenzae and Moraxella catarrhalis[J].J Infect Chemother,2018,24(2):83-87.
[4]HERATH SC,POOLE P.Prophylactic antibiotic therapy for chronic obstructive pulmonary disease(COPD)[J/CD].Cochrane Database Syst Rev,2013,28(11):CD009764.
[5]罗迪青,周晓琳,余敏君,等.不同培养时间与培养基pH值对体外实验中喹诺酮类抗解脲脲支原体药物敏感性的影响[J].中华医院感染学杂志,2007,17(9):1048-1050.
[6]IRWIN NJ,MCCOY CP,CARSON L.Effect of pH on the in vitro susceptibility of planktonic and biofilm-grown Proteus mirabilis to the quinolone antimicrobials[J].J Appl Microbiol,2013,115(2):382-389.
[7]唐映红,伍参荣,魏云,等.盐酸左氧氟沙星体内外抗菌作用研究[J].医药导报,2007,26(9):983-986.
[8]邹军,李欣欣,昭徐,等.左氧氟沙星对幽门螺杆菌体外抗菌活性的评价[J].中国抗生素杂志,2003,28(5):292-294.
[9]DEVANEY J,CURLEY GF,HAYES M,et al.Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia[J].Crit Care,2013,17(2):R82.
[10]OLSEN KM,GENTRY-NIELSEN M,YUE YM,et al.Effect of Ethanol on Fluoroquinolone Efficacy in a Rat Model of Pneumococcal Pneumonia[J].Antimicrob Agents Chemother,2006,50(1):210-219.
[11]CONTE JJ,GOLDEN JA,MCIVER M.Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects[J].Int J Antimicrob Agents,2006,28(2):114-121.
[12]TUNITSKAYA VL,KHOMUTOV AR,KOCHETKOV SN,et al.Inhibition of DNA Gyrase by Levofloxacin and Related Fluorine-Containing Heterocyclic Compounds[J].Acta Naturae,2011,3(4):94-99.
[13]AHMAD I,BANO R,SHERAZ MA.Photodegradation of levofloxacin in aqueous and organic solvents:a kinetic study[J].Acta Pharm,2013,63(2):223-229.
[14]XU K,BEN W,LING W,et al.Impact of humic acid on the degradation of levofloxacin by aqueous permanganate:Kinetics and mechanism[J].Water Res,2017,123:67-74.
[15]PEA F,DI QUAL E,CUSENZA A,et al.Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia[J].Clin Pharmacokinet,2003,42(6):589-598.