Study On Clinical Pharmacokinetics And Pharmacodynamics Of Flurbiprofen Axetil

0bjective1. An HPLC method was developed for detemination of the active metabolites flurbiprofen(FP) in the plasma of human.2. To study the pharmacokinetics of flurbiprofen axetil in patients of different age and gender groups under general anesthesia.3. To evaluate effects of controlled analgesia and stress with flurbiprofen axetil combined with small dose of fentanyl in patients undergoing hysterectomy surgery.Method1. The flurbiprofen was extracted from plasma and the applied column was Nova-Pak C18 (150 mm×4. 6 mm , 5μm). The mobile phase was consisted of methanol-water-phosphoric acid (68:32:0.0011). Flurbiprofen was detected by UV absorption at 247 nm. Injection volume was 20μL.. 2. Pharmacokinetics: 24 patients were randomly administered with 1㎎·kg-1 of flurbiprofen axetil to investigate the pharmacokinetic profiles. Subsequently,the plasma concentrations of FP were determined by HPLC. The data were analyzed by 3P97 program to get pharmacokinetics parameters,and the differences of main pharmacokinetics parameters were compared between different age or gender groups.3. Pharmacodynamics: 30 cases of ASAⅠ～Ⅱpatients undergoing hysterectomy surgery under general anesthesia were randomly divided into two groups: patients of Group FA received intravenous injection of flurbiprofen axetil at the dose of 1 mg·kg-1 before induction of anesthesia. 2 mg·kg-1 Flurbiprofen axetil, 0.010 mg·kg-1 fentanyl, 12mg ondansettron plus sodium lactate Ringer's injection to 100mL in PCA pump of Group FA. Patients of Group FE received intravenous injection of sodium lactate Ringer's injection 5mL before induction of anesthesia. 0.015 mg·kg-1 Fentanyl, 12mg ondansettron plus sodium lactate Ringer's injection to 100mL in PCA pump of Group FE. MAP and HR were recorded before induction of anesthesia(baseline),at the time of induction of anesthesia, tracheal intubation, during skin incision and tracheal outtubation. The analgesia effects were assessed by VAS score of pain, Ramesay sedation score, and the number of being pressed of PCA pump by the patients at 0h,4h,8h,16h and 24h after operation and probable complications such as mausea , vomiting and so on. Blood samples were obtained for determination of plasma IL-6,IL-10,PGE2 concentrations by ELISA before induction of anesthesia(baseline) and at 0h,6h and 24h after operation .Resuits1. Flurbiprofen concentration in plasma was determinated by HPLC. The calibration curve was ? = 0.1897x + 0.0147,(r = 0.9995,n = 8) and standard curve was liner in the range of 0.05～35μg·mL– 1. Recovery rate of FP was 99.9%with RSD less than 5%(n = 5).The RSD of intra-day and inter-day assays were both less than 5%(n = 5)and sensitivity was 0.050μg·mL-1(S/N≥3).2. The concentration-time curves of FP were conformed to a two-compartment open model,and only MRT and t1/2βwas significantly different among different age groups ,and no significant difference between male and female patients was found in the pharmacokinetics parameters aspect.3. At the time of tracheal intubation, MAP of Group FE was significantly higher (P﹤0.01)and HR was higher (P﹤0.05)than those of Group FA. At the tracheal outtubation, MAP of Group FE was higher than that of Group FA(P﹤0.05). Ramesay sedation score of Group FA at 0h after operation was significantly lower than that of Group FE(P﹤0.01); and at 4h after operation was lower than that of Group FE(P﹤0.05).VAS was significantly lower in Group FA at 0h,4h,8h,16h and 24h compared with that in Group FE(P﹤0.01). The number of being pressed of PCA pump was lower in Group FA than that of Group FE(P﹤0.05).The occurrence of lethargy, dizziness in group FA was less than that in Group FE(P﹤0.05).The concentrations of IL-6,IL-10 were significantly increased at 0h,6h and 24h after operation comparing to baseline (P<0.05); the concentration of IL-6 was significantly lower at 0h,6h after operation in Group FA than that of Group FE(P﹤0.05); the concentration of IL-10 was significantly higher at 0h,6h and 24h after operation in Group FA than that of Group FE(P﹤0.05).The concentration of PGE2 was lower at 0h,6h and 24h after operation in Group FA than that of Group FE, but there was no significantly statistics difference(P>0.05).