Effect Of Zhengtian Pill On Pharmacokinetic Parameters Of Phenytoin Sodium And Carbamazepine In Rats

PurposeThe effects of Zhengtian Pill on the activity of cytochrome P450 enzymes were observed by observing the effects of Zhengtian Pill on the pharmacokinetic parameters of two classical antiepileptic drugs,phenytoin and carbamazepine.Through the third-level hospital in Tai’an City,the statistical information on the use intensity of antiepileptic drugs in 2013-2018,the intensity of anti-epileptic drugs in various departments and the medical records of patients with epilepsy in 2018 were collected to understand the clinical use of anti-epileptic drugs.Provide theoretical basis and experimental data for clinical combination drugs,adverse reactions,etc.,to ensure clinical rational drug use,to achieve individualized drug delivery.MethodTwenty healthy SD rats were randomly divided into two groups,10 in each group.The experimental group was given Zhengtian Pills+DPH+CBZ,and the control group was given normal saline+DPH+CBZ.Continuous administration for three days,free feeding and water in the first two days,fasting for 12 hours before the third day of administration,and water for 2 hours..Group A（experimental group）:Zhengtian Pills6g·kg^-1(10ml·kg^-1),ig,qd×3d.Phenytoin(50mg·kg^-1)and carbamazepine(40mg·kg^-1)were given intragastrically 1 hour after the last administration;Group B（control group）:same dose of normal saline for 3 days,1 hour after the last administration Phenytoin(50mg·kg^-1)and carbamazepine(40 mg·kg^-1)were administered by gavage.0.5,1,1.5,2,3,4,6,8,12,18,24h after administration,0.5 ml of blood was taken from the posterior venous plexus in an anticoagulation centrifuge tube,and the blood sample was taken at 3000°C/min at 4°C.After centrifugation for 10 min,100μl of the upper layer plasma was stored in a 1.5 ml centrifuge tube at 4°C for storage.HPLC method was established,using methanol-water as the mobile phase and UV detector.By adjusting the flow ratio,select the appropriate wavelength and mobile phase flow rate,and take the phenobarbital as the internal standard to determine the peak area of the sample and bring it into the standard curve to calculate the concentration.The plasma concentrations of phenytoin and carbamazepine were fitted using the DAS 2.0 pharmacokinetic program and the pharmacokinetic parameters were calculated.Use the WHO-recommended daily dose（DDD）and refer to the DDD values recommended by the 16th edition of the New Pharmacy and the drug specifications,DDDs=annual application（g）/DDD for each breed Limited Daily Expenses（DDC）=sales amount of a drug/DDDs of the drug;average annual growth rate（AARG）（AARG）=[（year-end data/earning year data）^{1/（year-year-year）}-1]×100%.ResultThe results of this experiment show that Zhengtian Pill can significantly change the pharmacokinetic parameters of DPH and CBZ rats.Compared with the control group,the AUC_0-tand AUC_0-∞of DPH and CBZ in the experimental group increased significantly,and the AUC_0-t of DPH increased from（285.266±24.597）mg/L·h to（348.390±35.177）mg/L·h,AUC_0-∞increased from（355.171±39.536）mg/L·h to（516.056±41.974）mg/L·h;CBZ AUC_0-t from（89.017±44.848）mg/L·h（158.003±31.08）mg/L·h,AUC_0-∞increased from（92.721±56.352）mg/L·h to（176.660±46.06）mg/L·h,with significant difference（P<0.05）.Compared with the control group,the experimental group had an increase in C_max and a delay in T_max.The C_max of DPH increased from（17.735±4.967）mg/L to（20.986±6.011）mg/L,T_max was delayed by（7.52±2.33）h to（5.012±1.024）h;The C_max of CBZ was increased from（10.877±1.331）mg/L to（12.374±0.940）mg/L,T_max was delayed by（4.138±0.624）h to（5.472±1.058）h.The difference was significant（P<0.05）.After combined with Zhengtian Pill,the elimination rate constant K₁₀ and the overall clearance rate CL/F decreased significantly.The elimination rate constant K₁₀ of DPH decreased from（0.518±0.052）/h to（0.364±0.077）/h,and the overall clearance rate CL/F decreased from（0.147±0.008）to（0.097±0.007）;the elimination rate constant K₁₀ of CBZ decreased from（2.079±1.282）/h to（1.434±0.076）/h,and the overall clearance rate CL/F was（0.328±0.048）.)dropped to（0.227±0.091）.According to the statistical analysis of the use of anti-epileptic drugs in a top three hospital in Taian,it is known that the anti-epileptic drugs and the new drugs are equally important in the hospital.Sodium valproate still dominates for a long time in the future,and the proportion of new drugs increases.For the type of drugs,several anti-epileptic Chinese medicines can be appropriately introduced.ConclusionThis experimental study found that Tianwan can slow down the metabolic rate of DPH and CBZ in rats,and the half-life of the two antiepileptic drugs is prolonged.Combined with previous studies,it is speculated that Zhengtian Pill can inhibit the activity of CYP2C19 and CYP3A4,thereby reducing the metabolism of DPH and CBZ.Clinically,patients who are using DPH and CBZ in combination with Zhengtian Pill should pay attention to monitoring the blood concentration,timely adjust the dosage,prevent or reduce the occurrence of adverse reactions,and achieve safe,reasonable and effective treatment.With the development of medical technology and the reduction of drug prices,new anti-epileptic drugs will be favored by patients and doctors.The sales volume and frequency of drug use will gradually increase,and the market prospect is huge.