甲磺酸培氟沙星胶囊的人体药代动力学及相对生物利用度

８名受试者交叉口服甲磺酸培氟沙星片剂和胶囊各４００ｍｇ，用ＨＰＬＣ法测定血药浓度，灵敏度高，准确度好。测定血药浓度的时间曲线（除２例口服片剂符合一室模型外）均符合二室模型。片剂和胶囊的药动学参数，Ｃｍａｘ为５．７±１．５和６．８±１．７ｍｇ／Ｌ；Ｔ＿ｍａｘ为２．１±１．１和２．１±１．１ｈ；消除半衰期为１６±４和１５±６ｈ；胶囊的相对生物利用度１１４±１１％。关键词     

Pharmacokinetics of pefloxacin in renal insufficiency

Summary The kinetics of pefloxacin has been studied after a single intravenous infusion of 8 mg·kg^–1 in 15 male patients with various degrees of renal failure. No difference in distribution or elimination of the drug was observed between patients with mild or severe renal impairment. The mean volume of distribution (Vd area) and the mean plasma clearance were 2.03l·kg^–1 and 121.3 ml·min^–1, respectively. The mean apparent elimination half-life was 13.5 h. These values are close to those observed in healthy subjects. No accumulation of the active N-desmethylmetabolite was observed in cases of severe failure as compared to mild impairment; its apparent elimination half-life was about twice that of the parent drug. The efficacy of a 4 h haemodialysis in 6 additional anuric subjects done to remove pefloxacin from the body was poor.     

Pharmacokinetics and tissue distribution of intravenous pefloxacin for antibiotic prophylaxis in biliary surgery

The plasma levels and tissue penetration of pefloxacin were studied after prophylactic administration to patients undergoing elective biliary surgery. Pefloxacin was administered as a single dose of 800 mg given intravenously as an infusion 1 h before surgery. Over a period of two years, cultures of bile and stone were performed after cholecystectomy in order to find the main pathogens present in the geographical area of the hospital of Txagorritxu (Vitoria, Spain), as well as to test the antimicrobial susceptibility of these bacteria to pefloxacin. Thirty seven per cent of the bile and stone cultures were positive, and 75 different species were isolated. E. coli was the predominant microorganism (25%). Other frequent microorganisms were E. faecium (9.3%), S. epidermidis (6.6%) and Cl. perfringens (6.6%). Most species isolated were susceptible to pefloxacin, with MIC(90) values of 0.125 microg/ml for E. coli, 0.5 microg/ml for S. epidermidis and 1 microg/ml for Cl. perfringens. E. faecium was resistant, with a MIC(90) value of 8 microg/ml but a MIC(50) of 4 microg/ml (intermediate). After pefloxacin infusion, adequate drug plasma levels (>MIC(90)) for the most frequent pathogens were found throughout the procedure. Elimination half-life was estimated as 22.03+/-6.91 h; the area under the concentration-time curve from zero to infinite had a value of 275.07+/-130.02 mg h/l and the values for volume of distribution at steady-state and plasma clearance were 96.48+/-28.65 L and 3.60+/-1.83 l/h, respectively. Bile pefloxacin concentrations generally exceeded the minimum inhibitory concentrations for most relevant pathogens. Drug levels in gallbladder and subcutaneous tissues were also above the MIC(90) for extended periods. Patients were observed daily throughout their hospital stay. This included examination of the surgical wound and recording of body temperature. No cases of anaerobic infection were noted in the study patients. Other constants such as hospitalization stay and time of recuperation were normal for this type of surgery. According to these results, pefloxacin presents many features that make it suitable for use as a therapeutic prophylactic agent, such as its broad spectrum of antimicrobial activity and favorable pharmacokinetic properties.     

Evaluation of Bayesian estimation in comparison to NONMEM for population pharmacokinetic data analysis: Application to pefloxacin in intensive care unit patients

The pharmacokinetics of pefloxacin (PF) were investigated in a population of 74 intensive care unit patients receiving 400 mg bid as 1-hr infusion using (i) Bayesian estimation (BE) of individual patient parameters followed by multiple linear regression (MLR) analysis and (ii) NONMEM analysis. The data consisted of 3 to 9 PF plasma levels per patient measured over 1 to 3 dosage intervals (total 113) according to four different limited (suboptimal) sampling 3-point protocols. Twenty-nine covariates (including 15 comedications) were considered to explain the interpatient variability. Predicted PFCLfor a patient with median covariates values was similar in both BE/ MLR and NONMEM analysis (4.02 and 3.92 L/hr, respectively). Bilirubin level and age were identified as the major determinants of PFCLby both approaches with similar predicted magnitude of effects (about 40 and 30% decrease of median CL,respectively). Confounding effects were observed between creatinine clearance (26% decrease of PF CLin the BE/MLR model), simplified acute physiology score (a global score based on 14 biological and clinical variables) (18% decrease of median CLin the NONMEM model) and age (entered in both models) which were highly correlated in our data base. However, both models predicted similar PF CLfor actual subpopulations by using actual covariate values. Finally, the NONMEM analysis allowed identification of an effect of weight on CL(decrease of CL for weight <65 kg) whereas the BE/MLR analysis predicted an increase of CLin patients treated with phenobarbital. In conclusion, both approaches allowed identification of the major risk factors of PF pharmacokinetics in ICU patients. Their potential use at different stages of drug development is discussed.     

丁胺卡那霉素在烧伤早期家兔体内的药动学变化

11只正常家兔和10只20%体表面积三度烫伤家兔静脉注射丁胺卡那霉素(10mg/kg)的药动学资料比较发现,烫伤后6～12h 的丁胺卡那霉素血浓度明显上升(P<0.01),半衰期T_(?)延长(P<0.01),中央室分布容积Vc 和表观分布容积Vd 均减少(P 分别<0.01和<0.05);烫伤后36～42h 的丁胺卡那霉素血浓度较烫伤前下降,Vc 和Vd 增大。结果表明,烧伤早期随着渗出动态变化而改变的丁胺卡那霉素药动学不同于烧伤高代谢期的药动学。     

Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment

Summary Twenty patients (aged 26–70 years) with severely impaired renal function received pefloxacin twice daily for 5 days as 12 mg·kg^–1 administered as a 1 h i.v. infusion, or 800 mg administered as tablets.On Day 5 the minimal and maximal plasma concentrations were 5.9 and 11.5 mg·l^–1 respectively, after the infusion, and 8.0 and 10.4 mg·l^–1, respectively, after oral administration. The steady-state level of the N-desmethyl metabolite ranged from 0.9 (infusion) to 1.2 mg·l^–1 (oral route), and that of the N-oxide metabolite ranged from 6.2 (infusion) to 9.0 mg·l^–1 (oral route). The minimal concentration of unchanged drug was related to the age of the patients (infusion), but the N-oxide concentration was influenced by the degree of renal impairment (both routes).The pefloxacin levels were similar to those achieved in healthy subjects, but reduced renal function leads accumulation of its biotransformation products, especially of the N-oxide metabolite which lacks antibacterial activity.     

Pharmacokinetics of amikacin in cystic fibrosis: A study of bronchial diffusion

Summary 36 pharmacokinetic studies of amikacin were performed to evaluate the bronchial diffusion of amikacin in 9 children with cystic fibrosis, 3 to 15 years old. Amikacin was administered i.v. according to a variable dosage regimen. Four children without cystic fibrosis were enrolled as controls. The mean half life was 1.1, the volume of distribution averaged 0.26 l/kg, and the mean plasma clearance was 131 ml/min/1.73 m², which no differed from that of the controls. The mean peak plasma concentration was always above the MIC but its level depended on the unit dose: 18.5 mg/l, 25,95 mg/l and 31,46 mg/l for doses of 5, 7.5 and 12.5 mg/kg, respectively. Between consecutive amikacin infusions, the plasma level was above the MIC for 21% and 46% of the time after the 5 and 7.5 mg/kg doses. The maximum concentration in sputum between H1 and H2 was always below the MIC, except after 15 mg/kg. The ratio AUC sputum/AUC plasma was between 0.028 and 0.61, and it increased from the beginning to the end of the course of treatment. No side effects were observed on hearing, or vestibular and renal function. The results are used to suggest more appropriate dosing regimens.     

Oral pharmacokinetics and ascitic fluid penetration of pefloxacin in cirrhosis

Summary Plasma and ascitic fluid concentrations of pefloxacin in 10 cirrhotic patients and 8 healthy volunteers were determined following administration of a single oral dose of 400 mg.The mean elimination half-life was significantly increased in the patients (29.0 h) compared to in 8 healthy volunteers (12.3 h). In patients, the total plasma clearance (2.71 vs 6.85 l/h) and volume of distribution (1.12 vs 1.67 l/kg) were decreased. Estimated by the ratio of the AUC in peritoneal fluid and plasma, ascitic fluid penetration was 68% after one oral dose, and pronounced accumulation of pefloxacin in ascites was found after repeated doses.Oral pefloxacin would seem to be a convenient and useful treatment of spontaneous, gram-negative, bacterial peritonitis in cirrhosis. However, the decreased hepatic metabolism of the drug leads to a marked accumulation in plasma and ascites after repeated doses, and a reduced dose is required in these patients.     

培氟沙星及诺氟沙星对慢性阻塞性肺疾病患者氨茶碱药物动力学的影响

目的量化地研究培氟沙星(PFLX)及其代谢产物诺氟沙星(NFLX)对肺阻塞性疾病患者氨茶碱(Ami)药物动力学的影响.方法18例慢性阻塞性肺疾病(COPD)患者poAmi100mg,q8h,d4起第Ⅰ组(9例)加服PFLX400mg,q12h;第Ⅱ组(9例)加服NFLX400mg,q12h.至d9,以高效液相色谱色(HPLC)平行监测合用前后茶碱(Theo)的经时血浓,拟合Theo药物动力学参数并做统计学比较.结果与合用前相比,第Ⅰ组患者血清中Theo浓度显著增高(P<0.05),消除半衰期非常显著性延长(P<0.01),清除率显著下降(P<0.05);第Ⅱ组患者血清中Theo浓度也有所增加,消除半衰期相应延长,清除率相应减少,但均无统计学差异(P>0.05).结论合用PFLX对Ami的消除动力学有显著性抑制,临床合用时应注意Theo的血浓监测,防止Ami因代谢减慢而引起蓄积中毒NFLX与Ami合用则相对安全.     

培氟沙星口服给药的药物动力学研究

本文采用高效液相色谱法和微生物法测定血清与尿中培氟沙星（ＰＦＬＸ）浓度，研究８名健康志愿受试者单次口服ＰＦＬＫ片剂４００ｍｇ（２片）后及６名临床抗感染治疗患者每次口服ＰＦＬＸ片剂４００ｍｇ，每１２ｈ次，连续用药７ｄ期间的药物动力学特征，结果表明：ＰＦＬＸ片剂单剂量口服给药符合开放性二室模型特征，具有吸收迅速，分布广泛，消除半衰期长，原形药物及主要代谢物诺氟沙星尿药浓度高等特点，多剂量给药达稳态浓度     

氨苄青霉素对丁胺卡那霉素药动学的影响

本文采用微量微生物法对ＡＭＫ单用及ＡＭＫ与ＡＭＰ合用后，兔体内ＡＭＫ血、尿药浓度进行测定；药时数据用ＭＣＰＫＰ软件经ＩＢＭ计算机处理，并对两组药动学参数进行了统计学处理。结果表明ＡＭＰ对ＡＭＫ的药动学有显著的影响。     

Evaluation of population pharmacokinetic models for amikacin dosage individualization in critically ill patients

Objectives The aim of this study was to evaluate the reliability for dosage individualization and Bayesian adaptive control of several literature‐retrieved amikacin population pharmacokinetic models in patients who were critically ill. Methods Four population pharmacokinetic models, three of them customized for critically‐ill patients, were applied using pharmacokinetic software to fifty‐one adult patients on conventional amikacin therapy admitted to the intensive care unit. An estimation of patient‐specific pharmacokinetic parameters for each model was obtained by retrospective analysis of the amikacin serum concentrations measured (n = 162) and different clinical covariates. The model performance for a priori estimation of the area under the serum concentration‐time curve (AUC) and maximum serum drug concentration (C_max) targets was obtained. Key findings Our results provided valuable confirmation of the clinical importance of the choice of population pharmacokinetic models when selecting amikacin dosages for patients who are critically ill. Significant differences in model performance were especially evident when only information concerning clinical covariates was used for dosage individualization and over the two most critical determinants of clinical efficacy of amikacin i.e. the AUC and C_max values. Conclusions Only a single amikacin serum level seemed necessary to diminish the influence of population model on dosage individualization.     

Effects of isolation housing and timing of drug administration on amikacin kinetics in mice

目的：研究社会环境及给药时刻对小鼠阿米卡星代谢的影响．方法：小鼠按饲养环境：隔离饲养（Ｉ）或集体饲养（Ａ）及给药时间：日中（Ｄ）及午夜（Ｎ）随机分为：Ｉ－Ｄ，Ｉ－Ｎ，Ａ－Ｄ，Ａ－Ｎ４组．饲养４周后于Ｄ（１３∶００）或Ｎ（０１∶００）ｓｃ阿米卡星１５ｍｇ·ｋｇ－１，测定给药后其血浆浓度，以开放一室模型拟合并计算有关药代动力学参数．结果：Ａ－Ｎ组阿米卡星清除率较Ａ－Ｄ及Ｉ－Ｎ组增大，血浆半衰期变短，０－１小时血浆浓度时间曲线下面积（ＡＵＣ（０－１））较Ｉ－Ｎ组减少．隔离饲养两组（Ｉ－Ｄ，Ｉ－Ｎ）间药代动力学参数无显著差异．结论：社会环境及给药时刻均显著影响小鼠阿米卡星代谢动力学．     

不同给药途径对家兔阿米卡星药动学参数的影响

目的 :研究肌注和鼻甲注射对家兔阿米卡星 (AMK)药动学参数的影响。方法 :8只家兔予AMK 4mg·kg-1,im ,2wk后再以鼻甲注射同等剂量的AMK ,分别于给药后不同的时间点取血。通过荧光偏振免疫法 ,测定AMK的血药浓度 ,获得不同的药动学参数。结果 :肌注和鼻甲注射AMK后 ,Ke ,cmax和AUC均无显著性差异 ,而Ka ,T1/2 (Ka) ,tmax均有显著差异 (P <0 0 0 1) ;但鼻甲注射方法的达峰浓度较肌注高。结论 :鼻甲注射AMK后吸收较肌注迅速 ,两者的消除相似     

阿米卡星经纤维支气管镜和静脉给药的药动学比较

目的 :比较阿米卡星 (AMK)气管内与静脉给药后药动学参数的差异。方法 :对 16例肾功能正常 ,采用不同给药方法 ,使用AMK治疗的住院患者 ,用TDX法测定血药浓度 ,分析药动学参数。结果 :显示两种给药途径的药时曲线均符合二室模型 ,主要药动学参数比较无显著差异 (P >0 .0 5 ) ,气管内给药的绝对生物利用度为 94 % ,疗效确切。结论 :采用气管内给药法 ,可降低血药浓度 ,增加用药的安全性     

新抗精神病药物阿立哌唑的药代动力学

阿立哌唑具有稳定多巴胺和5-羟色胺系统的作用，作为一类新的抗精神病药物，应用于临床，已在中国上市。本文主要就阿立哌唑在人体的药代动力学特征及与其他药物的相互作用做一综述。     

迭代二步法估算阿米卡星的群体药动学参数

目的：用迭代二步法估算阿米卡星的群体药动学参数。方法：收集58例呼吸系统感染病人静脉滴注阿米卡星的临床血药浓度监测数据,用荧光偏振免疫法测定阿米卡星血药浓度。用迭代二步法估算阿米卡星的群体及个体药动学参数。比较性别、年龄、体重、肌酐清除率等因素对药动学参数的影响。结果：性别对药动学参数无影响,CL与CLcr呈正相关,Vd与体重呈正相关。结论：迭代二步法能较好地估算出阿米卡星的群体及个体药动学参数,用于优化给药方案及预测血药浓度可满足临床需要。     

Achilles tendinitis induced by pefloxacin and other fluoroquinolone derivatives

Four cases have been reported to the Netherlands Pharmacovigilance Foundation LAREB of Achilles tendinitis, as a suspected adverse reaction to pefloxacin. More than 20 cases of tendinitis and tendon rupture have previously been described in the literature in association with pefloxacin and various other fluoroquinolone derivatives. The mechanism involved is still unknown. Tendon disorders as an adverse drug reaction are very rarely reported to the WHO Collaborating Centre for International Drug Monitoring. The exception is in association with fluoroquinolone derivatives. More information is needed with regard to the frequency of tendinopathy during the use of pefloxacin and the other drugs in this group. Patients using a fluoroquinolone derivative should be informed on the risk of developing tendinitis and tendon rupture.     

Pharmacokinetics of intravenously administered ciprofloxacin in intensive care patients with acute renal failure

The pharmacokinetics of ciprofloxacin after a single intravenous administration of 100 mg were studied in intensive care patients with an acute renal impairment. There was no correlation found between the creatinine clearance and the renal clearance of ciprofloxacin. This applies to the entire group of patients. The decrease in renal clearance of ciprofloxacin was, however, more pronounced than the change in the elimination half-life, suggesting an important extra-renal elimination of the drug.     

烧伤高代谢期家兔丁胺卡那霉素药物动力学的改变

３０只家兔烫伤前和烫伤后静脉注射丁胺卡那霉素（１０ｍｇ／ｋｇ）的药动学资料比较的结果表明，２０～３０％体表面积三度烫伤后１周、２周和３周家兔的丁胺卡那霉素血浓度均明显降低；药动学参数也均表现为：半衰期（Ｔ１／２）缩短、分布容积（Ｖ１和Ｖｄ）增加、清除率（ＣＬ）增加和曲线下面积（ＡＵＣ）减少。