Effect Of Pazufloxacin Mesilate On Pharmacokinetics Of Doxofylline

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.