Assessment Of Effects Of Drugs On Cytochrome P450 Isforms Activity Of Rats By A Five-drug Cocktail Approach

Aim: To study the influence of AGS and RT on the activities of cytochromeP450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4, then provide guidance for clinical rational administration.Methods: "Cocktail" approach was used to evaluate the influence of AGSand RT on the activities of cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of 5 specific probe drugs caffeine, tolbutamide, omeprazole, chlorzoxazone and midazolam respectively for 5 isoforms. Rats were randomly divided to test group and control group, and were administrated by test drugs (AGS, RT) and blank solvent respectively for 7 consective days, then injected the mixture of 5 probes through vena caudalis on the 8^th day, and soon after the blood samples were obtained through extirpating the eyeballs at a series of time-points. The concentrations of probe drugs in plasma were measured by a gradient HPLC method with UV detection. The effects of test drugs on the activities of cytochrome P450 isoforms were judged indirectly by comparing the pharmacokinetic parameters of test group with those of control group.Results: 1. In the experiment for AGS, the t_1/2β of 5 probe drugs of rats in test group and control group respectively were: caffeine 2.31±0.12 and 2.21±0.43h; tolbutamide 5.79±0.47 and 5.28±0.29h; omeprazole 0.34±0.10 and 0.23±0.10h; chlorzoxazone 0.71±0.06 and 0.57±0.04h; midazolam 0.67±0.14 and 0.57±0.31h. There was a statistically significant difference in the t_1/2β of chlorzoxazone between two groups analyzed by /-test, and no statistically significant difference in the t_1/2β of other four probes.2. In the experiment for RT, the t_1/2β of 5 probe drugs of rats in test group and control group respectively were: caffeine 4.84±1.50 and 3.34±1.06h; tolbutamide 5.62±0.80 and 10.37±0.34h; omeprazole 0.50±0.16 and 0.34±0.02h; chlorzoxazone 1.02±0.10 and 0.74±0.10h; midazolam 0.36±0.12 and 0.33±0.07h. There was a statistically significant difference in the t_1/2β of tolbutamide and chlorzoxazone between two groups analyzed by t-test, and no statistically significant difference in the t_1/2β of other three probes.Conclusions: 1. AGS could inhibit the activity of cytochrome P450 2E1 ofrats, and had no effects on the activities of CYP1A2, CYP2C9, CYP2C19 and CYP3A4.2. RT could induce the activity of CYP2C9 and inhibit the activity of CYP2E1, but had no effects on the activity of CYP1A2, CYP2C19 and CYP3A4.