【作者】 李峰；

【导师】 阚全程；

【作者基本信息】 郑州大学 ， 药理学， 2007， 硕士

【摘要】 多索茶碱（Doxofylline，Dox），化学名为1，3-二甲基-7-（1，3-二氧环戊烷-2-基）甲基-3，7-二氢-1H-嘌呤-2，6-二酮，是一种新型的甲基黄嘌呤类支气管扩张剂。与茶碱相比具有疗效较强，耐受性好，不良反应少等特点，在治疗支气管哮喘等方面有望成为茶碱的替代品。Ⅱ期临床实验表明，多索茶碱与茶碱控释片不良反应发生率分别为19.6％和20.8％（P＞0.05），临床应用需要进行血药浓度监测。甲磺酸帕珠沙星（Pazufloxacin mesilate，PZFX）是第三代氟喹诺酮类抗菌药，抗菌谱广，抗菌活性强，不良反应少，有可能成为临床上广泛应用治疗各种感染性疾病的常用药物。有关部门预计到2020年，哮喘等慢性阻塞性肺病（COPD）可能成为导致人类死亡的第三大病因，甲磺酸帕珠沙星合并多索茶碱使用，可能成为很好的用药方案。研究发现，氟喹诺酮类药物能不同程度地抑制茶碱类药物的代谢，降低茶碱类药物的清除率、延长半衰期，使体内血药浓度升高，从而引起多种不良反应的发生。有关甲磺酸帕珠沙星对多索茶碱药动学的影响的研究，国内外未见报道。本实验分别以家兔和健康人为试验对象，考察达稳态时PZFX对Dox药动学的影响，为临床合理用药提供理论依据。材料与方法：（1）本实验对Dox和PZFX合用家兔、健康人体内药动学进行了研究，采用自身对照设计，分设Dox单用组及其与PZFX合用组。（2）以高效液相色谱法（high performance liquid chromatograghy HPLC）平行监测合用PZFX前后血清中Dox的血药浓度。流动相：含1‰三乙胺的乙腈-0.02M磷酸盐缓沖液（15：85，pH6.5～6.7）；流速：0.8mL．min^-1；柱温：30℃；检测波长：273nm。（3）所有采集血样经二氯甲烷与异丙醇（95：5）混合萃取液提取，流动空气吹干，甲醇溶解进样。本法测得血清中Dox可达基线分离，合用PZFX后，其它组分对Dox的色谱峰无干扰。用多索茶碱和内标峰高比与浓度进行线性回归，标准曲线显示家兔体内Dox在0.10N20.0 mg．L^-1范围内、健康人体内Dox在0.5～20.0 mg．L^-1范围内均呈良好的线性关系（r²=0.9968和r²=1.0000）。稳定性好，家兔和健康人血清中Dox平均回收率分别为100.7％和98.63％；精密度高，家兔和健康人的日内差分别＜7.67％和＜4.69％，日间差分别＜6.68％和＜4.68％。（4）药时数据经3P97软件处理。结果：Ⅱ家兔药动学试验：单用组d1～4 ig给予Dox 30mg／kg，q12h，至稳态，于第4天晨灌服Dox后不同时间耳缘静脉取血；合用组于第4天晚Dox用法不变情况下加用PZFX 30mg／kg，缓慢静脉推注，q12h，于第7天晨ivPZFX、灌服Dox后不同时间耳缘静脉取血。处理血样，测定合用药前后Dox的血药浓度。结果：（1）单用及合用PZFX后Dox在家兔体内呈一室模型。（2）合用前后Dox的药动学参数：Ke分别为0.148±0.038h^-1，0.134±0.020h^-1；Ka分别为17.63±17.30h^-1，11.32±10.81h^-1；T_1／2α分别为0.119±0.126h，0.164±0.158h；T_1／2β分别为4.946±1.146h，5.293±0.790h；V／F_c分别为6.448±4.789L／kg，5.562±4.027L／kg；均无显著差异性（P＞0.05）。而达峰时间T_max由0.580±0.503h增加到0.769±0.583h（P＞0.05），延长了32.6％；一个给药周期内的时间-浓度曲线下面积AUC_0-12^ss由37.535±16.686mg．h．L^-1增加到45.136±22.159 mg．h．L^-1（P＜0.05），增加了20.25％；血浆清除率CL／F由0.904±0.627L．kg^-1．h^-1下降到0.751±0.575 L．kg^-1．h^-1（P＜0.05），降低了16.9％；达稳态时Dox的峰浓度和谷浓度分别由合用前的6.00±3.04mg．L^-1、1.19±0.58mg．L^-1增加到6.87±3.81 mg．L^-1、1.67±0.83mg．L^-1，分别增加了14.4％和39.5％（P＜0.05）。Ⅱ健康人药动学试验：单用组d1～4 po给予Dox 400mg，q12h至稳态，于第4天晨口服Dox后不同时间肘静脉取血；合用组于第4天晚Dox用法不变情况下加用PZFX 300mg，ivgtt，q12h，于第7天晨ivgtt PZFX、口服Dox后不同时间取另一侧肘静脉血。处理血样，测定合用药前后Dox的血药浓度。结果：（1）单用及合用PZFX后Dox在体内呈一室模型。（2）合用前后DOX的药动学参数：Ke分别为0.14±0.04h^-1，0.12±0.04h^-1；T_1／2α分别为0.29±0.15h，0.16±0.13h；C_max分别为11.88±3.43mg／L，12.61±3.09mg／L；V／F_c分别为30.73±9.79L／kg，30.14±6.64L／kg；均无显著差异性（P＞0.05）。而达峰时间T_max由1.23±0.42h减少到0.82±0.42h，提前了33.0％（P＜0.05）；Ka由3.03±1.55h^-1增加至5.64±2.12h^-1，增加了85.82％（P＜0.05）；消除半衰期T_1／2β由合用前的5.39±1.47h增加至6.45±1.59h，延长了19.6％（P＜0.05）；一个给药周期内的时间-浓度曲线下面积AUC_0-12^ss，由85.12±23.90mg．h．L^-1增加到92.84±25.72 mg．h．L^-1，增加了9.07％（P＜0.05）；血浆清除率CL／F由4.07±1.19L．kg^-1．h^-1下降到3.46±1.23 L．kg^-1．h^-1，降低了15.1％（P＜0.05）；稳态Dox的谷浓度由合用前的2.57±1.09mg．L^-1增加到合用后的3.83±1.67mg．L^-1，增加了48.9％（P＜0.05）。结论：在该给药剂量下，达稳态时甲磺酸帕珠沙星不影响多索茶碱在家兔体内的分布，但可升高其血药浓度，增加药时曲线下面积，降低清除率。在该给药剂量下，达稳态时甲磺酸帕珠沙星不影响多索茶碱在健康人体内的分布，多索茶碱的峰浓度的升高亦无统计学意义，但可增加药时曲线下面积，延长消除半衰期，降低清除率。本研究提示临床长期合用两药时，应予以重视，配合血药浓度监测，进行多索茶碱个体化给药，避免因药物相互作用带来的不良后果。更多还原

【Abstract】 Doxofylline （Dox）, 7-（methylictheoflline）-l,3-dioxane, is a new-type xanthine antibronchial spasmodic drug. Compared with aminophylline, Dox boasts high curative effect and low position, and it probably replace aminophylline to cure chronic bronchitis. The phase II clinical practice indicates that the rates of occurance of the adverse effects of Dox and TP are 19.6% and 20.8% respectively, there is no notable statistical difference between them（P>0.05）. Therefore, TDM is needed in clinical practice.Pazufloxacin mesilate （PZFX）, a newly developed fluoroquinolone, shows broadspectrum, potent antimicrobacterial activity and lower toxicity than conventional quinolones. It is forecasted that chronic obstructive pulmonary disease （COPD） maybe the third morbid reason for human beings’ death by 2020. Therefore, it will be a good treatment for COPD by using Dox combined with PZFX.However, researchers have shown that fluoroquinolones can restrain the metabolism of TP to different degrees. They can reduces the clearance of TP, lengthened the elimination half-life time of TP so that the serum concentration of TP can be raised which finally bring ADRs. The reports concerning the influence of PZFX on the pharmacokinetics of Dox are absent at home and abroad. This paper focuses on the influence when the two are used together at steady state.Materials and Methods （1） This experiment aims at the study of the pharmacokinetics of Dox alone and its combination with PZFX in rabbits and healthy volunteers. The study is conducted by using a crosser design. （2） The concentration of Dox in blood is detected by high-performance liquid chromatography （HPLC）. Mobile phase: acetonitrile: 0.02M KH₂PO₄ buffer （15:85 v/v pH6.5～6.7） consists of 1‰triethypamine. Flow rate: 0.8mL/min. The peaks are monitored with UV at 273nm. The column temperature was maintained at 30°C. （3） All of the specimens are extracted by dichloromethane and isopropanol and are evaporated to dryness. The residue is reconstituted with mobile phase, and subjected to HPLC analysis. Dox in blood can be separated from the baseline very well by this method. After combination of PZFX, the chromategrafhic peak of Dox can be detected without any other interferences. The regression between concentrion and peak height shows that Dox has a good linear relationship. The detecting method is stable and precise. （4） The concentration-time data are disposed with 3P97 programe.Results I The pharmacokinetics in rabbits: Dox alone was given as 30mg/kg oral dose, ql2h, for 4 days. Serum samples were obtained on day 4 at indicaed time before and after using Dox. From the fourth day evening, concomitant administration of PZFX （30mg/kg）, q12h, was commenced. Serum samples were obtained on the seventh day at indicaed time before and after using Dox. The results are as follows: （1） The concentration-time curve in Dox alone and comdined groups are adequately fitted one-compartment open model. （2） The parameters such as Ke, Ka, T_1/2a, T_1/2β, V/F_c are 0.148±0.038h^-1 and 0.134±0.020h^-1, 17.63±17.30h^-1 and 11.32±10.81h^-1, 0.119±0.126h and 0.164±0.158h, 4.946+ 1.146h and 5.293±0.790h, 6.448±4.789L/kg and 5.562±4.027L/kg, no significant （P>0.05） . After the combination of PZFX , the rated of increase of AUC_0-12^ss, C_max and C_min, compared with using Dox alone, were 20.25%, 14.4% and39.5%, respectively. CL/F value for Dox decreased significantly, by 16.9%.II The pharmacokinetics in healthy volunteers: Dox alone was given as 400mg oral dose, ql2h, for 4 days. Serum samples were obtained on day 4 at indicaed time before and after using Dox. From the fourth day evening, concomitant administration of PZFX （300mg）, dissolved in 100mL of saline, q12h, was commenced. Serum samples were obtained on the seventh day at indicaed time before and after using Dox. The results are as follows: （1） The concentration-time curve in Dox alone and comdined groups are adequately fitted one-compartment open model. （2） The parameters such as Ke, T_1/2a, C_max and V/F_c are 0.14±0.04h^-1 and 0.12±0.04h^-1, 0.29±0.15h and 0.16±0.13h, 11.88±3.43mg/L and 12.61±3.09mg/L, 30.73±9.79L/kg and 30.14±6.64L/kg, no significant （P>0.05） . After the combination of PZFX , the rated of increase of T_1/2β, AUC_0-12^ss and C_min, compared with using Dox alone,were 19.6%, 9.07% and48.9%, respectively （P<0.05） . CL/F value for Dox decreased significantly, by 15.1%.Conclusions This finding suggests that Pazufloxacin mesilate can slightly inhibit metabolism of doxofylline at steady state and increase Dox concentration in serum. Moreover, the serum concentration of Dox in both rabbits and health volunteers are very different so that careful monitoring of Dox levels is recommended if the use of the two drugs in clinical combination therapy is necessary.更多还原