多索茶碱和左氧氟沙星联合应用的药动学
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摘要
慢性阻塞性肺病(chronic obstructive pulmonary diseases，COPD)是常见的慢性呼吸道疾病，发病率高，病程漫长，被WHO报道为是位于心血管疾病、脑血管疾病和急性呼吸道感染之后，和艾滋病并列的全球第四大死亡原因。临床上，氟喹诺酮类(fluoroquinolones FQNLs)和茶碱类药物合用治疗COPD较为普遍。
大量研究表明，FQNLs和茶碱类药物合用，时有茶碱类药物不良反应发生。研究发现，FQNLs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，使茶碱类药物体内血药浓度升高。有关FQNLs影响茶碱类药物药动学的机理尚无定论。但目前认为，作为旋转酶抑制剂，FQNLs抑制茶碱类药物代谢的机制很可能在于其抑制细胞色素氧化酶P-450的某一亚类(CYP1A2)，而研究表明，茶碱类黄嘌呤药物的代谢又主要通过肝脏CYP1A2酶来完成的。这就更加证明，由于FQNLs对肝药酶有不同程度的抑制作用，影响到茶碱类药物在肝脏的代谢，使其在体内蓄积，易致中毒。
多索茶碱(doxophylline Dox)是一种新近研制出的用于支气管阻塞性肺病的新型黄嘌呤类药物，治疗效果是氨茶碱的10—15倍，在治疗支气管痉挛方面可能成为氨茶碱的替代品。文献报道，Dox与茶碱相似，血药浓度在20μg／ml以上为中毒浓度，Ⅱ期临床试验表明，本品与茶碱控释片不良反应发生率分别为19.6％与20.8％，无显著性差异(P＞0.05)，临床应用需要进行TDM。左氧氟沙星(levofloxacin LVFX)是氧氟沙星的光学活性L—型异构体，LVFX以其更高的抗菌活性，较少的不良反应和药动学方面优于其它FQNLs的优点而在临床广泛
郑州大学2004届硕士研究生毕业论文
多索茶碱和左氧氟沙星联合应用的药动学研究
应用。LVFX和Dox联合应用的药动学研究国内外均未见报道。本文报道Dox
和LVFX合用时，LvFx对Dox药动学的影响。
材料与方法(l)本文对Dox和LVFX合用健康人、病人体内药动学进行了研
究，健康人体内试验采用自身对照试验设计，病人体内试验采用平行对照试验设
计，分设Dox单用组及其与LVFX合用组。(2)以高效液相色谱法(high
performanee liquid chromato『即hy HPLC)检测血清中Dox浓度，流动相:含l
%0三乙胺的乙睛一。.02mol/L磷酸二氢钠缓冲液(巧:85)(PH二6.7一石.9)，流速:
1.omL加in，柱温:30℃，检测波长:273nm。(3)所有采集血样经二氯甲烷与异
丙醇混合萃取液提取，空气流吹干，流动相溶解进样。本法测得血清中Dox可
达基线分离，在合用LVFx后，Dox的色谱峰无其它组分干扰。用峰高与浓度进
行回归，标准曲线示Dox在0.05一8.0 pg八nl范围内有良好的线性关系
(Y= 0.9999)。稳定性好，血清中Dox平均回收率为104.7%。精密度高，日内
差<5%，日间差<8%。(4)药时数据经3P97软件处理。
结果I健康人体药动学试验:单用组单次静脉滴注Dox 300mg后不同时间
肘静脉取血;合用组先单次静脉滴注LvFx 400mg，继之静脉滴注Dox，用药剂量、
方法及血样收集均同单用组。结果:(l) Dox单用组及其与LVFX合用组的药时
曲线均符合二房室模型;(2)单用组及合用组经时血药浓度分别为(5 min)
3 .13士0.64和3.33士0.87 p g/mL;(10min)2.47士0.57和2.66士0.58 p g/inL:(15min)
1 .95士0.47和2.54士o.53p留mL;(30mi功1.66=1=0.41和1.83士o.45pg/mL:(lh)1.42士0书
和1 .48士0.3 1 p g/mL;(Zh)0.76土0.19和0.7矢o.18p目InL:(3h)0.4肚0.16和
0 .4肚0.12p留mL;( 4h)0.21士0.08和0.28士0.12 p g/mL:(6h)0.08士0.03和
0.09士o.o3p留mL:(3)单用组及合用组的VC、tl二。、tl二，、从1、KI。、K;2、AUC、
CLs等药动学参数分别为6.07土2.13和33.92士29.90L;O‘05士0.01和0.33土o.27h;
2 .2肚0.05和1 .4肚0.25h;1 .3牡0.23和1 .06士o.39h一’;6.0狂1.45和2.51土2.12h一‘;
6 .77士1 .67和2.47士2.57h一’;15.5肚4.45和17.06士3.32(mg/L)·h;34.57士7.25和
35.16士9.26L爪。
n病人体内药动学试验:单用组静脉滴注Dox，临床常用量，3oomg，
q.d.连用六天，最后一天给药前及给药后不同时间肘静脉取血:合用组于用Dox
前，静脉滴注LvFx，临床常用量，400mg，q.d.连用六天，合用组Dox用药剂量、
郑州大学2004届硕士研究生毕业论文
多索茶碱和左氧氟沙星联合应用的药动学研究
方法及血样收集均同单用组。结果:(1) Dox单用组及其与LVFX合用组的药时
曲线均符合二房室模型;(z)单用组与合用组的经时血药浓度为(5 min) 4.33士1 .17
和4.66士1 .11“助扯‘(巧min) 3.87士。脚和420士Q男p动nl‘(3伍而n)3.47士0.为和3.79士
0.80p助斌(lh) 2.79士O茄和3.08士0.58p的11‘(黝)1.82士035和2.05士039p动111名仲公
0.80士。26和Q叫士。朋p加1几归习036士0.19和Q科士o20p助侧3)单用组及合用组的
Ve、tl二。、tl二，、及1、Kl。、K12、AUC、CLS等药动学参数分别为26.53士11.77
和19.20士8.28L:0.05士0.01和0.04士0.olh:1.72士0.44和1.80士0.4lh:6.31士0.78
和5 .96士1 .ogh一’;1 .02士0.37和2 .44士1 .49h一’:7.76士3.56和11.19士4.o3h一l:31.06
士6 .29和35.28士7.02(mg/L)·h:23.64士5.02和20.78士4.77L/h。
结论用配对资料的t检验和两样本均数的t检验
Chronic obstructive pulmonary diseases(COPD), a common category of human respiratory disease with high morbidity, has become the fourth leading cause for death in the world. In clinical practice, the patients with COPD often receive the combined therapy of fluoroquinolones (FQLNs) and theophylline(TP).
However, researches have shown that adverse effects of TP always accompany the combination of FQLNs and TP. Studies have revealed that FQNLs can restrain the metabolism of TP to different degrees. It reduces the clearance of TP, lengthened the elimination half-life time of TP which finally raised the serum concentration of TP. The principles of the influences of FQNLs on the pharmacokinetics of TP are not clear now. Many researchers hold at present that, as the inhibitor of rotating enzyme, the principles of the inhibition of FQNLs on the metabolism of TP mainly lie in the inhibition of one subclass of the cytochrome oxidase (CYP1A2). However studies have shown that xanthine drugs are metabolized by CYP1A2 in the liver chiefly, which further proves that the different degrees of fluoroquinolones' inhibition on hepatic cytochrome oxidase hampers the metabolism of TP, which is apt to accumulate intoxication.
Doxophylline (Dox), a new-type xanthine drug, has recently been developed to treat COPD. Compared with TP, Dox boasts high curative effect and low poison, hi the treatment of bronchial spasm, Dox, which is ten to fifteen times as effective as TP, has the prospect of becoming the substitute of TP. Documents indicate that toxic concentration of Dox is beyond 20ugtaL , which is similar to TP. 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, the researches of the influences of FQNLs on the pharmacokinetics of Dox are needed for directing the doctors to use drugs reasonably. Levofloxacin (LVFX) is the (L-) optical isomer of floxacin. It is widely used in clinical practice thanks to its advantage of more activity against bacteria and less adverse effect. However, the reports concerning the influence of LVFX on the pharmacokinetics of Dox are absent at home and abroad. This paper focuses on the influence when the two drugs are used together.
Materials and Methods (1) This dissertation aims at the study of the pharmacokinetics of Dox alone and its combination with LVFX in healthy volunteers and patients. In healthy volunteers, the study is conducted by using a crosser design. In patients, it is done by using parallel design. (2) The concentration of Dox in blood is detected by high performance liquid chromatography(HPLC). Mobile phase:acetonitrile: 0.1M NaHPO buffer (15:85 v/v PH=6.7~6.9) consists of l%o triethypamine ; Flow rate: l.Oml/min; Ultraviolet wavelengh:273nm; column temperature:30癈. (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 LVFX, the chromatographic peak of Dox can be detected without any other interferences. The regression between concentration and peak height shows that Dox has a good linear relationship in the range of 0.05-8 U g/mL( Y =0.9999).The detecting method is stable with the average recovery of Dox 104.7% and is precise with the standard deviation among days below 8%, withindays below 5%. (4) The concentration-time data are disposed with 3P97
programe.
Results I The pharmacokinetics in healthy volunteers: Dox alone group: Dox 300mg ivgtt; Dox+LVFX group: LVFX 400mg ivgtt, followed by Dox 300mg ivgtt. The serum sample was collected at indicated time after the use of Dox .The results are as follows: (1) The concentration-time curve in Dox alone and combined groups are adequately fit to two-compartment open model;(2) The concentration of Dox in Dox alone and combined groups are: (5min) 3.13?.64
大量研究表明，FQNLs和茶碱类药物合用，时有茶碱类药物不良反应发生。研究发现，FQNLs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，使茶碱类药物体内血药浓度升高。有关FQNLs影响茶碱类药物药动学的机理尚无定论。但目前认为，作为旋转酶抑制剂，FQNLs抑制茶碱类药物代谢的机制很可能在于其抑制细胞色素氧化酶P-450的某一亚类(CYP1A2)，而研究表明，茶碱类黄嘌呤药物的代谢又主要通过肝脏CYP1A2酶来完成的。这就更加证明，由于FQNLs对肝药酶有不同程度的抑制作用，影响到茶碱类药物在肝脏的代谢，使其在体内蓄积，易致中毒。
多索茶碱(doxophylline Dox)是一种新近研制出的用于支气管阻塞性肺病的新型黄嘌呤类药物，治疗效果是氨茶碱的10—15倍，在治疗支气管痉挛方面可能成为氨茶碱的替代品。文献报道，Dox与茶碱相似，血药浓度在20μg／ml以上为中毒浓度，Ⅱ期临床试验表明，本品与茶碱控释片不良反应发生率分别为19.6％与20.8％，无显著性差异(P＞0.05)，临床应用需要进行TDM。左氧氟沙星(levofloxacin LVFX)是氧氟沙星的光学活性L—型异构体，LVFX以其更高的抗菌活性，较少的不良反应和药动学方面优于其它FQNLs的优点而在临床广泛
郑州大学2004届硕士研究生毕业论文
多索茶碱和左氧氟沙星联合应用的药动学研究
应用。LVFX和Dox联合应用的药动学研究国内外均未见报道。本文报道Dox
和LVFX合用时，LvFx对Dox药动学的影响。
材料与方法(l)本文对Dox和LVFX合用健康人、病人体内药动学进行了研
究，健康人体内试验采用自身对照试验设计，病人体内试验采用平行对照试验设
计，分设Dox单用组及其与LVFX合用组。(2)以高效液相色谱法(high
performanee liquid chromato『即hy HPLC)检测血清中Dox浓度，流动相:含l
%0三乙胺的乙睛一。.02mol/L磷酸二氢钠缓冲液(巧:85)(PH二6.7一石.9)，流速:
1.omL加in，柱温:30℃，检测波长:273nm。(3)所有采集血样经二氯甲烷与异
丙醇混合萃取液提取，空气流吹干，流动相溶解进样。本法测得血清中Dox可
达基线分离，在合用LVFx后，Dox的色谱峰无其它组分干扰。用峰高与浓度进
行回归，标准曲线示Dox在0.05一8.0 pg八nl范围内有良好的线性关系
(Y= 0.9999)。稳定性好，血清中Dox平均回收率为104.7%。精密度高，日内
差<5%，日间差<8%。(4)药时数据经3P97软件处理。
结果I健康人体药动学试验:单用组单次静脉滴注Dox 300mg后不同时间
肘静脉取血;合用组先单次静脉滴注LvFx 400mg，继之静脉滴注Dox，用药剂量、
方法及血样收集均同单用组。结果:(l) Dox单用组及其与LVFX合用组的药时
曲线均符合二房室模型;(2)单用组及合用组经时血药浓度分别为(5 min)
3 .13士0.64和3.33士0.87 p g/mL;(10min)2.47士0.57和2.66士0.58 p g/inL:(15min)
1 .95士0.47和2.54士o.53p留mL;(30mi功1.66=1=0.41和1.83士o.45pg/mL:(lh)1.42士0书
和1 .48士0.3 1 p g/mL;(Zh)0.76土0.19和0.7矢o.18p目InL:(3h)0.4肚0.16和
0 .4肚0.12p留mL;( 4h)0.21士0.08和0.28士0.12 p g/mL:(6h)0.08士0.03和
0.09士o.o3p留mL:(3)单用组及合用组的VC、tl二。、tl二，、从1、KI。、K;2、AUC、
CLs等药动学参数分别为6.07土2.13和33.92士29.90L;O‘05士0.01和0.33土o.27h;
2 .2肚0.05和1 .4肚0.25h;1 .3牡0.23和1 .06士o.39h一’;6.0狂1.45和2.51土2.12h一‘;
6 .77士1 .67和2.47士2.57h一’;15.5肚4.45和17.06士3.32(mg/L)·h;34.57士7.25和
35.16士9.26L爪。
n病人体内药动学试验:单用组静脉滴注Dox，临床常用量，3oomg，
q.d.连用六天，最后一天给药前及给药后不同时间肘静脉取血:合用组于用Dox
前，静脉滴注LvFx，临床常用量，400mg，q.d.连用六天，合用组Dox用药剂量、
郑州大学2004届硕士研究生毕业论文
多索茶碱和左氧氟沙星联合应用的药动学研究
方法及血样收集均同单用组。结果:(1) Dox单用组及其与LVFX合用组的药时
曲线均符合二房室模型;(z)单用组与合用组的经时血药浓度为(5 min) 4.33士1 .17
和4.66士1 .11“助扯‘(巧min) 3.87士。脚和420士Q男p动nl‘(3伍而n)3.47士0.为和3.79士
0.80p助斌(lh) 2.79士O茄和3.08士0.58p的11‘(黝)1.82士035和2.05士039p动111名仲公
0.80士。26和Q叫士。朋p加1几归习036士0.19和Q科士o20p助侧3)单用组及合用组的
Ve、tl二。、tl二，、及1、Kl。、K12、AUC、CLS等药动学参数分别为26.53士11.77
和19.20士8.28L:0.05士0.01和0.04士0.olh:1.72士0.44和1.80士0.4lh:6.31士0.78
和5 .96士1 .ogh一’;1 .02士0.37和2 .44士1 .49h一’:7.76士3.56和11.19士4.o3h一l:31.06
士6 .29和35.28士7.02(mg/L)·h:23.64士5.02和20.78士4.77L/h。
结论用配对资料的t检验和两样本均数的t检验
Chronic obstructive pulmonary diseases(COPD), a common category of human respiratory disease with high morbidity, has become the fourth leading cause for death in the world. In clinical practice, the patients with COPD often receive the combined therapy of fluoroquinolones (FQLNs) and theophylline(TP).
However, researches have shown that adverse effects of TP always accompany the combination of FQLNs and TP. Studies have revealed that FQNLs can restrain the metabolism of TP to different degrees. It reduces the clearance of TP, lengthened the elimination half-life time of TP which finally raised the serum concentration of TP. The principles of the influences of FQNLs on the pharmacokinetics of TP are not clear now. Many researchers hold at present that, as the inhibitor of rotating enzyme, the principles of the inhibition of FQNLs on the metabolism of TP mainly lie in the inhibition of one subclass of the cytochrome oxidase (CYP1A2). However studies have shown that xanthine drugs are metabolized by CYP1A2 in the liver chiefly, which further proves that the different degrees of fluoroquinolones' inhibition on hepatic cytochrome oxidase hampers the metabolism of TP, which is apt to accumulate intoxication.
Doxophylline (Dox), a new-type xanthine drug, has recently been developed to treat COPD. Compared with TP, Dox boasts high curative effect and low poison, hi the treatment of bronchial spasm, Dox, which is ten to fifteen times as effective as TP, has the prospect of becoming the substitute of TP. Documents indicate that toxic concentration of Dox is beyond 20ugtaL , which is similar to TP. 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, the researches of the influences of FQNLs on the pharmacokinetics of Dox are needed for directing the doctors to use drugs reasonably. Levofloxacin (LVFX) is the (L-) optical isomer of floxacin. It is widely used in clinical practice thanks to its advantage of more activity against bacteria and less adverse effect. However, the reports concerning the influence of LVFX on the pharmacokinetics of Dox are absent at home and abroad. This paper focuses on the influence when the two drugs are used together.
Materials and Methods (1) This dissertation aims at the study of the pharmacokinetics of Dox alone and its combination with LVFX in healthy volunteers and patients. In healthy volunteers, the study is conducted by using a crosser design. In patients, it is done by using parallel design. (2) The concentration of Dox in blood is detected by high performance liquid chromatography(HPLC). Mobile phase:acetonitrile: 0.1M NaHPO buffer (15:85 v/v PH=6.7~6.9) consists of l%o triethypamine ; Flow rate: l.Oml/min; Ultraviolet wavelengh:273nm; column temperature:30癈. (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 LVFX, the chromatographic peak of Dox can be detected without any other interferences. The regression between concentration and peak height shows that Dox has a good linear relationship in the range of 0.05-8 U g/mL( Y =0.9999).The detecting method is stable with the average recovery of Dox 104.7% and is precise with the standard deviation among days below 8%, withindays below 5%. (4) The concentration-time data are disposed with 3P97
programe.
Results I The pharmacokinetics in healthy volunteers: Dox alone group: Dox 300mg ivgtt; Dox+LVFX group: LVFX 400mg ivgtt, followed by Dox 300mg ivgtt. The serum sample was collected at indicated time after the use of Dox .The results are as follows: (1) The concentration-time curve in Dox alone and combined groups are adequately fit to two-compartment open model;(2) The concentration of Dox in Dox alone and combined groups are: (5min) 3.13?.64
引文
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11. Shihabi ZK, et al. Review of drug analysis with direct serum injecton
on the HPLC column [Review]. J Lip Chromatogr, 1988,11:1579-93
12．卢佩章．HPLC法及其专家系统．第一版．沈阳：科技出版社，1992：231
13. Grossi E, Franzone JS, et al. Doxofylline: pharmacolki profile and a review of clinical studies[J]. Riv Eur Sci Med Farmacol, 1988;10(5): 415-30
14. Bolona E, Lagana A, Terracino D et al. Oral and intravenous pharmacokinetic profiles of doxophylline in patients with chronic bronchitis [J]. ]Int Med Res, 1990,18(4): 282-8
15．周权、姚彤炜等。代谢性药物相互作用。临床药理杂志，2001，17(4)：313-318
16. Bachmann K A, Schwartz J I, et al. Predicting the ciprofloxacintheophylline interaction fromsingle plasma theophylline measurements[J]. Br J Clin Pharmacol, 1988, 26(2): 191-4
17. von Rosensteil NA, Adam D, et al. Macrolide antibacterials. Drug interactions of clinical significance[J]. Drug Saf 1995,13:105-22
18. Shimada N, Green CE, Chiba K, etal. Identification of human cytochrome P-450 involved in a drug metabolism and its application[J].Xenobio Metabol Dispos 1995,10,413-9
19. Upton RA, et al. Pharmacokinetic interactions between theophylline and other medication (part Ⅰ). Clin Pharmacokinet 1991,20:66-80
20. Upton RA, et al. Pharmacokinetic interactions between theophylline and other medication (part Ⅱ). Clin Pharmacokinet 1991,20:135-50
21. Nakamura H, Ohtsuka T, et al. Effect of levofloxacin on theophylline clearance during theophylline and clarithromycin combination therapy [J]. Ann Pharmacother 2001,35:691-93
22. Wijnands WJA, et al. Enoxacin decreased the clearance of theophylline in man. 8r J Clin Pharmacol, 1985: 20:583
23. Niki Y., Hashiguchi M, et al. Quinolone antimicrobial agents and theophylline. Chemotherapy (Tokyo),1992,40:598-601
24. Fuhr U, etal. Inhibitory potency of quinolone antibacterial agents against cytochrome P-4501A2 activity in vivo and in vitro. Antimicrob Agents Chemother, 1992, 36:942
25. Sorgel F, et al. Effects of 2 quinolone antibacterials, temafloxacin and enoxacin, on theophylline pharmacokinetics. Clin Pharmacokinet, 1992,22 (Suppl 1): 65
26．施毅等。环丙沙星和氧氟沙星对氨茶碱药物动力学的影响。中国临床药理学杂志，1994，10(4)：206
27. Muralidharan G, et al. The effects of tosufloxacin(TOS) on the metabolism of theophylline (THE) and the relationship to TOS drug level. [Abstract No. 1466] In: program and abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1990
28．张琰等。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。 中国临床药学杂志，2000，9(1)：18-21
29．徐小平，陈聪等。依诺沙星及左氧氟沙星对茶碱代谢影响的研究。中国抗生素杂志，1999，24(3)：213-214
30．李朵璐，阚全程。大鼠体内左氧氟沙星对多索茶碱药代动力学的影响。中国药业，2004，13(1)：42-43
31. Gisclon LG, et al. Absence of a pharmacokinetic interaction between intravenous theophylline and orally administered levofloxacin. J Clin Pharmacol, 1997, 37(8): 744-50
32．贾金广等。左氧氟沙星对慢性阻塞性肺病患者氨茶碱血浓度的影响。中国抗生素杂志，1999，24(增刊)：38
33．张永玲。乳酸左氧氟沙星对肺心病人体内茶碱药动学的影响。中国药业，2000，9(5)：12-13
34．黎月玲等。氧氟沙星对健康人茶碱药物动力学的影响。中国医院药学杂志，1997，17(9)：389-391
35．蒋淼等。氟罗沙星对肺心病人体内茶碱药物动力学的影响。中国医院药学杂志，
1998, 18 (10): 441—443
36. Bergogne-Berezin E, et al. Clinical role of protein binding of quinolones. Clin Pharmacokinet, 2002, 41(10):741-50
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8. Fuhr U, et al. Quinolone antibacterial agents: relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2. Mol Pharmacol, 1993;43(2):191-199
9. Wijnands WJA, Vree TB, et al. The influence of quinolone derivatives on theophylline clearance[J].Br J Clin Pharmac, 1986;22:677
10. Sorgel F, Kinzig M, et al. Pharmacokinetics of gyrase inhibitors, part 2: renal and hepatic elimination pathways and drug interactions[J]. Am J Med, 1993;94(suppl 3A):56S
11. Shihabi ZK, et al. Review of drug analysis with direct serum injecton
on the HPLC column [Review]. J Lip Chromatogr, 1988,11:1579-93
12．卢佩章．HPLC法及其专家系统．第一版．沈阳：科技出版社，1992：231
13. Grossi E, Franzone JS, et al. Doxofylline: pharmacolki profile and a review of clinical studies[J]. Riv Eur Sci Med Farmacol, 1988;10(5): 415-30
14. Bolona E, Lagana A, Terracino D et al. Oral and intravenous pharmacokinetic profiles of doxophylline in patients with chronic bronchitis [J]. ]Int Med Res, 1990,18(4): 282-8
15．周权、姚彤炜等。代谢性药物相互作用。临床药理杂志，2001，17(4)：313-318
16. Bachmann K A, Schwartz J I, et al. Predicting the ciprofloxacintheophylline interaction fromsingle plasma theophylline measurements[J]. Br J Clin Pharmacol, 1988, 26(2): 191-4
17. von Rosensteil NA, Adam D, et al. Macrolide antibacterials. Drug interactions of clinical significance[J]. Drug Saf 1995,13:105-22
18. Shimada N, Green CE, Chiba K, etal. Identification of human cytochrome P-450 involved in a drug metabolism and its application[J].Xenobio Metabol Dispos 1995,10,413-9
19. Upton RA, et al. Pharmacokinetic interactions between theophylline and other medication (part Ⅰ). Clin Pharmacokinet 1991,20:66-80
20. Upton RA, et al. Pharmacokinetic interactions between theophylline and other medication (part Ⅱ). Clin Pharmacokinet 1991,20:135-50
21. Nakamura H, Ohtsuka T, et al. Effect of levofloxacin on theophylline clearance during theophylline and clarithromycin combination therapy [J]. Ann Pharmacother 2001,35:691-93
22. Wijnands WJA, et al. Enoxacin decreased the clearance of theophylline in man. 8r J Clin Pharmacol, 1985: 20:583
23. Niki Y., Hashiguchi M, et al. Quinolone antimicrobial agents and theophylline. Chemotherapy (Tokyo),1992,40:598-601
24. Fuhr U, etal. Inhibitory potency of quinolone antibacterial agents against cytochrome P-4501A2 activity in vivo and in vitro. Antimicrob Agents Chemother, 1992, 36:942
25. Sorgel F, et al. Effects of 2 quinolone antibacterials, temafloxacin and enoxacin, on theophylline pharmacokinetics. Clin Pharmacokinet, 1992,22 (Suppl 1): 65
26．施毅等。环丙沙星和氧氟沙星对氨茶碱药物动力学的影响。中国临床药理学杂志，1994，10(4)：206
27. Muralidharan G, et al. The effects of tosufloxacin(TOS) on the metabolism of theophylline (THE) and the relationship to TOS drug level. [Abstract No. 1466] In: program and abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1990
28．张琰等。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。 中国临床药学杂志，2000，9(1)：18-21
29．徐小平，陈聪等。依诺沙星及左氧氟沙星对茶碱代谢影响的研究。中国抗生素杂志，1999，24(3)：213-214
30．李朵璐，阚全程。大鼠体内左氧氟沙星对多索茶碱药代动力学的影响。中国药业，2004，13(1)：42-43
31. Gisclon LG, et al. Absence of a pharmacokinetic interaction between intravenous theophylline and orally administered levofloxacin. J Clin Pharmacol, 1997, 37(8): 744-50
32．贾金广等。左氧氟沙星对慢性阻塞性肺病患者氨茶碱血浓度的影响。中国抗生素杂志，1999，24(增刊)：38
33．张永玲。乳酸左氧氟沙星对肺心病人体内茶碱药动学的影响。中国药业，2000，9(5)：12-13
34．黎月玲等。氧氟沙星对健康人茶碱药物动力学的影响。中国医院药学杂志，1997，17(9)：389-391
35．蒋淼等。氟罗沙星对肺心病人体内茶碱药物动力学的影响。中国医院药学杂志，
1998, 18 (10): 441—443
36. Bergogne-Berezin E, et al. Clinical role of protein binding of quinolones. Clin Pharmacokinet, 2002, 41(10):741-50