Preliminary Study On Activity Hepatic CYP450 3A4 And 2D6 In Pigs And The Effects Of Three Kands Veterinary Drugs

1 The activity studies of Midazolam CYP450 3A4 probe in pigsA rapid accurate and sensitive high performance chromatographic method was developed for the determination of activity of hepatic CYP450 3A4 in pigs with Midazolam probe.The calibration curves were linear over a wide range of concentrations (0.05～25μg/ml),and the detection limit of Midazolam was 0.05μg/ml.The precisions (RSD%,n=5) of within day and day to day were less than 6.5%and 15%,respectively.The pharmacokinetic characteristics of Midazolam in pigs after after oral administration 2 mg/kg were best described by an open two-compartment model with first order absorption rate.The main pharmacokinetic parameters were as follows,respectively:t1/2α:0.23±0.07 h,t1/2β:0.30±0.04 h,CL(s):2.10±0.55 L/h,AUC:0.97±0.17μg·h/mL.It is close with results in literature and showed that hepatic CYP 3A4 is acticve in pigs2 The activity studies of dextromethorphan P450 2D6 probe in pigThe activity of hepatic CYP450 2D6 were investigated with dextromethorphan probe in pig by HPLC method.The pharmacokinetic characteristics of dextromethorphan in pig after oral administration 1 mg/kg were best described by an open one-compartment model with first order absorption rate.The main pharmacokinetic parameters were as follows, respectively:t1/2α0.86±0.24 h,t1/2β2.58±0.22 h,CL(s),4.52±0.41μg·h/mL.it showed that the activity of hepatic CYP450 2D6 is active in health pigs.3 Study the effects of Doxycycline,Tiamulin and Cefquinome on the activity of hepatic CYP 450 3A4 and 2D6 in pigsThe effects of Doxycycline,Tiamulin and Cefquinome on the activity of hepatic CYP 450 3A4 and 2D6 in pigs was estimated with Midazolam and Dextromethorphan as probe. 24 pigs were randomly divided into control group(administered with physiological saline), Doxycycline-treated group(5mg/kg·bw,i.p.×7 d),Tiamulin-treated group(5mg/kg·bw, i.p.×7 d)and Cefquinome-treated group(1mg/kg·bw,i.p.×7 d).The plasma concentrations of Midazolam and Dextromethorphan were determined by HPLC.The pharmacokinetic parameters were estimated.The results:In the reach about CYP 3A4,Compared with the saline-treated control group,the T1/2βof Midazolam for Doxycycline and Tiamulin groups is were sharply prolonged(p＜0.01),and the Cefquinome group is significantly shorted(p＜0.01).The CL(s) for Doxycycline group is significantly decreased(p＜0.01),the Cefquinnime group is sharply increased.The AUC for Doxycyline group is sharply increased(p＜0.01),the Cefquinnime group is significantly deereased(p＜0.01).It is showed that activity of CYP 450 3A4 could be markedly inhibited by Doxycycline,and Cefquinome could be a strong inducer.In the reach about CYP 2D6,Compared with the control group,the T1/2βof Dextromethorphan for all the groups were sharply prolonged(p＜0.01).The CL(s) for Cefquinnime group is significantly decreased(p＜0.01). The AUC for Cefquinnime group is sharply inereased(p＜0.01).It is indicated that activity of CYP 450 2D6 could be strongly inhibited by Cefquinome.