| In the use of anti-tumor drugs, rational combination of different drugs has the effects of improving efficiency and redμcing toxicity and side effects; and the monitoring of the pharmacokinetics of the drugs combined is of great significance for chemotherapy. This study aims to establish a method using HPLC with double wavelength detection to determine the concentrations of CTX and DDP at one time, and preliminarily study their kinetics in rats.Use Wistar rats (clean level),200-220g weight,6-8w age, put them in the following conditions:temperatμre 20-24℃; moistμre 50%-60%; light-on for 12hs(08:00-20:00); light-off for the other 12hs; sound-proof; the rats are free to eat and drink. The rats are kept as described for 1w before being used in the experiment. DDP of 3.0mg/kg was injected through the tail vein in the first group; CTX of 100mg/kg was injected in the same way in the second group; and 3.0mg/kgDDP+75mg/kgCTX injected in the third group.0.5ml of blood was taken before the injection and at 10min,30min, 1h,2h,4h,8h, 10h,14h,20h,24h,48h,72h,96h after the injection and put 200μl rat plasma into glass-stopped tubes of 2.0ml.200μl of 0.5% sodium carbonate was mixed into the tμbes and then newly-produced DDTC of 100μl was mixed in. The tμbes were kept in water-bath of 37℃for 30min thereafter, the substance was abstracted by using1000μl of aether and the aether was removed with nitrogen flow in water-bath of 37℃. The remainder was dissolved in 100μl of the mobile phase; the concentrations of DDP and CTX in blood were detected using 20μl of the solution. The column was Hypersil-ODS2, mobile phase methanol—water (80:20); the concentrations were detected at the modes of 254nm and 195nm of the ultraviolet detector.The retention time of CTX is 5.15min, the linear range of the concentration curve is 0.5-10μg/ml, r=0.9998, with the detection limit of 0.1μg/ml(S/N≥3); the data for DDP are 9.26min,0.1-2.0μg/ml, r=0.9998, and 0.01μg/ml(S/N≥3) respectively. The kinetics cμrve of the CP solμtion displays the characteristics of two compartment model, the elimination half-life (t1/2β) of CTX is prolonged from 8.2h to 13.5h, the apparent volμme of distribμtion (Vd) improves from 6.1(L·kg-1) to 20.5(L·kg-1); the T1/2βof DDP is prolonged from 17.0h to 29.8h, the Vd improves from 4.6(L·kg-1) to 5.9(L·kg-1).This study preliminarily investigated the kinetics of the drugs in the CP Strategy, and compared the results with that of each drug. The kinetic data from animal experiment displayed CTX and DDP were distrubated a little faster in the CP solution (with the absorption half-life of 1.16h and 0.72h respectively) than used separately; while the elimination half-life was significantly longer (13.5h and 29.8h respectively) than used separately((7.2h and 17h respectively)), which showed used in combination the drugs were eliminated slower, their t1/2βwere significantly prolonged up to 42.3% with statistic significance(P<0.01) and the Vd were improved significantly, which helped prolong the presence of the drugs in the circulation system and improve their bioavailabilities. The clearance rate in the CP Strategy is lower than used separately, this indicates used in combination the doses and intervals of uses of DDP should be regulated-according to the 2w period(7.0 half-life) of full elimination of DDP,and CTX is four days,so the interval in CP should be at least 2w-and plenty saline should be given to avoid intoxication by accumulation. K10 used in combination of CTX and DDP are decrease by 75% and 60% respectively with statistic significance(P<0.01). This indicates elimination rate from central compartment decreases.And the parameters K12,K21 showed no significant difference. Used in combination the drugs show synergistic function, resulting in lower rate of clearance, which may be due to the same mechanism and target of effect of the drugs. But at the same time, it reveals an increase in the toxic and side effects of the two drugs, so it's essential to minitor the their concentrations in clinical administration. |
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