Effects Of Gemifloxacin On Pharmacokinetics Of Doxofylline

Gemifloxacin(GEMI), is a new study of fluorinated quinolone antibacterialagents of LG Life Sciences Ltd. It plays sterilization by inhibiting the bacteria's DNAspiral topoisomerase enzyme and VI. Comparing with other quinolone's activityagainst Gram-positive (G⁺) bacteria, GEMI 's Bactericidal activity is 4-64 times thanthe control drug. It has a powerful anti-gram-positive (G⁺) bacteria action; with regardto gram-negative (G^-) bacteria, GEMI has a similar bactericidal with ciprofloxacinand has a more powerful activity than lomefloxacin, ofloxacin and norfloxacin. GEMIis a great potential antibiotic drugs, it is used to deal with infections caused by variousbacteriums in clinical work. The United States FDA recommends GEMI as a directclinical treatment of bacterial infections.Doxofylline(DFL)is a new-type Methyl xanthine drug, which is recently beendeveloped. It is a bronchodilator and has a directly role on bronchi, it let the trachealsmooth muscle relax. The mechanism is by inhibiting the phosphodiesterase which isin the smooth muscle cells, so as to inhibit the asthma.it's Chinese Chemical Name is1,3-dimethyl-7-(1,3-dioxo-cyclopentene-based-2-base)methyl-3,7-dihydro-1H-purine-2,6-diketone. It is often used to do the treatment of chronic obstructive pulmonarydisease(COPD). The pharmacodynamic action is 10-15 times stonger thanaminophylline witch is similar with doxofylline, and there is no addiction, it has noside-effects on the central nervous system and cardiovascular system. It is expected tobe a substitute for aminophylline. There is a wide range of applications. It is the same as other xanthine derivatives, there will be a slight increase in heart rate, it alsoincrease gastric acid secretion, it can cause urine trace increase when it reach a certainconcentration. We have the the need for clinical application of therapeutic drugmonitoring(TDM).The research shows that when we use fluoroquinolone antibiotic drug togetherwith theophylline, it will come to show up a competitive inhibition of the binding siteof cytochrome P450, and so it inhibit the metabolism of theophylline in varyingdegrees, reducing the clearance rate of theophylline, after this, the half-life isextended, the result is that the concentration of theophylline increases and the toxicreaction appears. We should monitor the plasma concentration of theophylline in theclinical work. There have been a number of pharmacokinetic reports about thecombination of fluoroquinolone and theophylline, however, the study about thecombination of the GEMI and DFL is not reported now. This paper reports theinfluence on DFL's pharmacokinetic which is caused by GEMI, with a view toprovide a pharmacokinetic foundation for clinical rational use of drug.Materials and Methods (1) This experiment aims at the study of thepharmacokinetics of DFL alone and its combination with GEMI in rabbits and healthyvolunteers. The study is conducted by using a self-control design. (2) Theconcentration of DFL in blood is detected by high-performance liquid chromatogram-phy(HPLC). Mobile phase: Methanol:water(37:63). Flow rate: 1mL/min. The peaksare monitored with UV at 273nm. The column temperature is maintained at 25℃. (3)All of the specimens are extracted by dichloromethane and isopropanol and areevaporated to dryness. The residue is reconstituted with mobile phase, and subjectedto HPLC analysis. DFL in blood can be separated from the baseline very well by thismethod. After combination of GEMI, the chromategrafhic peak of DFL can bedetected without any other interferences. The regression between concentrion andpeak height shows that DFL has a good linear relationship. The detecting method isstable and precise. (4) The concentration-time datas are disposed with 3P97 programe.ResultsⅠ: The pharmacokinetics in rabbits: DFL alone group: DFL 30mg/kgoral dose, ql2h, for 3 days. Serum samples were obtained on day 4 at indicaed timebefore and after using DFL; DFL+GEMI group: GEMI 30mg/kg, followed by DFL 30mg/kg. Serum samples were obtained on the fourth day at indicaed time before andafter using DFL. The results are as follows: (1) The concentration-time curve in DFLalone and comdined groups are adequately fitted one-compartment open model. (2)The parameters such as Ka, Ke, T_1/2a, T_1/2β, T_max, AUC_0-12^ss, V/F_(c), CL/F are0.6050±0.2321h^-1 and 0.6550±0.3086h^-1 0.1225±0.0790h^-1 and 0.1360±0.0830h^-1,1.3118±0.5442h and 1.2535±0.4996h, 7.0348±2.8208h and 6.6401±3.1230h,3.6082±0.7452h and 3.3551±0.6965h, 100.6010±47.7007mg.h.L^-1 and 83.4599±49.3179mg.h.L^-1, 3.3216±0.8272L/kg and 4.5736±2.9034L/kg, 0.4546±0.4447Lkg^-1.h^-1 and 0.7441±0.8292L.kg^-1.h^-1, DFL reached steady state concentration of theValley are 1.4676±0.7554mg.L^-1 and 1.2192±0.6819mg.L^-1, no significant(P＞0.05).The parameters of C_max decreased from 6.4570±2.1245 mg. L^-1 to 5.5195±2.4744mg.L^-1P＜0.05).Ⅱ: The pharmacokinetics in healthy volunteers: DFL alone group: DFL 400mgoral dose, q12h, for 3 days. Serum samples were obtained on day 4 at indicaed timebefore and after using DFL; DFL+GEMI group: GEMI 320mg, q24h, followed byDFL 400mg. Serum samples were obtained on the fourth day at indicaed time beforeand after using DFL. The results are as follows: (1) The concentration-time curve inDFL alone and comdined groups are adequately fitted one-compartment open model.(2) The parameters such as Ka, Ke, T_1/2a, T_1/2β, C_max,T_max, AUC_0-12^ss, V/F_(c), CL/Fare 1.2358±0.4977h^-1 and 1.3721±0.7215h^-1, 0.1233±0.0643h^-1and 0.1368±0.0786h^-1,0.6720±0.3502h and 0.6208±0.2841h, 6.7034±2.5981h and 6.5622±3.0628h,12.8534±3.7552mg/L and 11.5207±5.0145mg/L, 2.2728±0.5668h and 2.1066±0.5004h, 167.7896±76.9727mg.h.L^-1 and 149.2195±87.2212mg.h.L^-1, 25.3403±6.9393L/kg and 33.1565±18.7188L/kg, 3.4557±3.0438L.kg^-1.h^-1 and 5.4835±6.0203L.kg^-1.h^-1, DFL reached steady state concentration of the Valley are3.06643±1.3935mg.L^-1and 2.5171±1.3530mg.L-l, no significant(P＞0.05).Conclusions (1) Under the conventional dose, we do the two drugs incombination and let it go to the Steady state in rabbits, Doxofylline mainpharmacokinetic parameters have no significant changes, Gemifloxacin does not havesignificantly affect on the pharmacokinetics of Doxofylline and does not cause the accumulation of Doxofylline. (2) Under the conventional dose, we do the two drugs incombination and let it go to the Steady state in healthy volunteers, Doxofylline mainpharmacokinetic parameters have no significant changes, Gemifloxacin does not havesignificantly affect on the pharmacokinetics of Doxofylline and does not cause theaccumulation of Doxofylline. (3)This study reveals that when we do the combinationof Doxofylline and Gemifloxacin in rabbits and healthy volunteers, Gemifloxacindoes not make the adverse reactions of Doxofylline increase, the combination isrelative safety, it provides a pharmacokinetics basis for Clinical rational drug use.