| Doxofylline(Dox),chemical name 7-methylictheofylline-l,3-dioxane,is anew-tyed xanthine drug. It has been developed to treat COPD.Compared with aminophylline, its curative function is 10-15 times in treatment of bronchiospasm,therefore it probably replace aminophylline and has a broad applied foreground. The phase II clinical practice indicates that the rates of occurance of the adverse effects of Dox and theophylline slow-released pill are 19.6% and 20.8% respectively, there is no notable statistical difference between them(P>0.05). TDM is needed in clinical practice.Gatifloxacine(GAT),as the new 8-methoxyl Florquinolones (FQNs), has broad antibacterial spectrum, more activity against bacteria. It has more perfect action on antiG+germ than sparfloxacin and ciprofloxacin . It is reported abroad that it has high bioavailability, rapid absorption, wide distribution, long elimination half time. GAT has important significance in the treatment of infectional dieases, especially in respiratory system.Chronic obstruvtive pulmonary diseases(COPD) , a common category of human respiratory diseas with high morbidity, has become the fourth leading cause for death in the world. In clinical practice, the patients with COPD often receive the integrated therapy of fluoroquinolones (FQNs) and theophylline(TP). However, researches have shown that adverse effects of TP always accompany the combination of FQNs and TP. Studies have revealed that FQNs can restrain the metabolism of TP to differentdegrees. It reduces the clearance of TP, lenghthened the elimination half-life time of TP, which finally raised the serum concentration of TP. This is apt to accumulate intoxication.However, the reports concerning the influence of GAT 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 experiment aims at the effects of GAT on pharmacokinetics of Dox in rabbits and healthy volunteers .. In rabbits, the study is conducted by using a parallel contrast design, and in health man, it is done by using personal design,both setting up the group of Dox alone and the gtoup of Dox combined with GAT. (2) The concentration of Dox in blood is detected by high performance liquid chromatography(HPLC). Mobile phase:acetonitrile: 0.1M NaH2PO4 buffer (15:85 v/v PH=6.7~6.9) consists of \%o triethypamine ; Flow rate: l.Oml/min; Ultraviolet wavelengh:273nm; column temperature:30°C. (3) All of the specimens are extracted by dichloromethane and isopropanol and are evaporated to dryness. The residue is reconstituted with methanol,then introduced sample. Dox in blood can be separated from the baseline very well by this method. After combination of GAT, the chromatographic peak of Dox can be detected without any other interferences. The regression between concentration and ratio of peak area of Dox and internal standard shows that Dox has a good linear relationship in the range of 0.05-32 u g/mL( Y =0.9997).The detecting method is stable with the average recovery of Dox 104.99% and is precise with the standard deviation withindays below 5%, among days below 8%. (4)The concentration-time data are disposed with DAS ver 1.0 programe. Results I The pharmacokinetics in rabbits: Dox alone group: Dox 25mg/kg, iv ,once;Dox+GATgroup:first GAT25mg/kg iv,qd for six days;in the last day,after administration GAT, followed by Dox,dose> methods and sample collection are same as "Dox alone group"o The results are as follows: (1) The concentration-time curve in Dox alone and combined groups are adequately fitted two-compartment open model;(2) The concentration of Dox in Dox alone and combined groups are: (5min)13.91±2.75and 5.08±4.02/*g/mL;(10min)10.78±2.45 and 12.14±2.91/*g/mL;(15min)8.37±1.89 and 11.59±2.68g/mL;(30min)7.11±1.61and8.05±2.25/ig/mL;(lh)6.00±157and6.94±1.40/ag/m L;(2h)3.29±0.84and3.73±0.79/ig/mL;(3h)1.61±0.63andl.82±0.61^g/mL;(4h)0.84±0.31a ndl.25±0.62/^g/mL;(6h)0.31±0.11and0.38±0.13^g/mL(3)The parameters in single group and combinational group of Vd> ti/2a> ti/2B> K2^ Kio, Kn, AUC, CLs are respectively 1.04 ± 0.15andl.20 ± 0.69 L/Kg; 3.15 ± 0.77and21.23 ± 34.51min; 75.68 ± 7.72and85.67±31.95min0.015±0.0021and0.013±0.0045min'1;0.14±0.039and0.13±0.18 mm-1;0.032±0.008and0.0076±0.0025mm1;1070.8±278.3andl267.3±?51.45(mg/L) ? mi n;0.024±0.006and0.02±0.0062L/min.II The pharmacokinetics in volunteers: Dox alone group: Dox 300mg ivgtt, once, The serum samples were collected at indicated time before and after the use of Dox Dox+GAT group: GAT 300mg ivgtt, for 6 days, q.d., in the last day,after administration GAT followed by Dox 300mg ivgtt, dose, methods and sample collection are same as "Dox alone group"o The results are as follows: (l)The concentration-time curve in Dox alone and combined groups are adequately fitted two-compartment open model; (2)The serum concentration of Dox in single group and combined group are: (5min) 2.818+0.5762 and 2.9990±0.7844jugmL; (lOmin) 22220+0.5156 and 2.3790+ 0.4962; (15min)1.7520±0.4260 and 22940±a4772MgtoL^30min)1.4980+03741 and 1.6270+ 03670^ml4(lh)12620+a4058 and 1.380±03052ugtoU(2h)0.680±0.174 and 0.7O)±0.159/#nL; (3h)03570 ± 0.1417 and 03560 ± 0.1087 ; (4h)0.1850 + 7jO12E and 02510 + 0.1091/Mg4nIX6h)5.670EO2+4266EO2 and d80OB hw^ K21* Ki0, K^ AUC, CLs 63.76+11.30 |P 73.69+47.70L/Kg; 3.11+0.68 |P 21.81+32.01min; 76.59+7.11 fP 96.30+46.19min; 0.02±0.002 IP 0.01 + 0.007mm-1; 0.16±0.035 ^1 0.23 ±0.41 nun'1; 0.09+0.025 ^P 0.03+0.029 min"1; 220.70 ±64.84 |P 290.51 ± 154.12(mg/L) ? min; 1.36+0.36 |P 1.13±0.40L/min<,Conclusions Statistical analysis was conducted by two independent-samples t test and paired t-test.(D In rabbits: After the combination of GAT, there was no significantly difference (P>0.05) of serum concentration in combined groups. According to the fitted pharmacokinetical parameters,after combined with GAT, the main pharmacokinetical parameters' diversification of Dox are as follows:k2i> CLs declined a little, Vd, t\a?,AUC increased a little.but no significene(P>0.05); a ? K12declined and tu2<.increased significantly(F<0.05). When Dox was administered with GAT in rabbits, the Dox elimination process was not influenced significantly but the distribution was changed, Vck ti/2?increased,but didn't result in Dox accumulation.nor increased its advert reaction obviously, the combination of GAT and Dox was relatively safe. (2) In volunteers:after the combination of GAT, the serum concentration of Dox at indicated time all increased slightly, and there were no significant differences between the two groups(P>0.05). According to the fitted pharmacokinetical parameters,after combined with GAT, the main pharmacokinetical parameters' diversification of Dox are as follows:k2i > CLs declined a little;Vd > AUC ^ i\a? increased a little ,but no significene(P>0.05); a ? K12 declined and t1/2? increased significantly(P<0.05). When Dox was administered with GAT in health man, the Dox elimination process was not influenced significantly but the distribution was changed, VcL ti / 2=increased,but didn't result in Dox accumulation,nor increased its advert reaction obviously, the combination of GAT and box was relatively safe The results indicate that the combination of GAT do not influence the metabolizable pharmacokinetics of Dox. It is relatively safe to use the two drugs together. This dissertation, with its significant theoretical and practical implications, may provide the basis of pharmacokinetis for the use of the two drugs in clinical combination therapy.
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