Study On Pharmacokinetics And Relative Bioavailability Of Tetrahydroclovir And Its Solid Dispersions In Mice And Dogs

Object:This study use PEG4000as the supplementary material to make THC-solid dispersion, examing the dissolution rate of THC in different proportion to detremin the best ration between THC and PEG4000, at last, infrared spectroscopy was uesed to verification the formation of THC-solid dispersion.To study pharmacokinetic properties of THC, a fast sensitive, reproducible LC-MS/MS method with good resolution and simultaneous detection of analytes was developed and successfully applied for pharmacokinetic evaluation in mice and Beagles plasma following oral administration to determine THC. Compare the pharmacokinetic parameters and relative bioavailability in same dose, and then providing a basis for the medicinal development and process optimization and clinical applications of THC.Methods:200SPF KM mice and16healthy adult Beagle dogs, male and female, were randomly divided into two groups, oral administration in fasted state with THC and THC-solid dispersion,then determine the concentrations of THC in mice blood plasma by HPLC-MS/MS before and after administrate THC and THC-solid dispersion for15min,30min,45min,1h,1.5h,2h,3h,4h,6h,24h, and determine the concentrations of THC in Beagle blood plasma by HPLC-MS/MS before and after administrate THC and THC-solid dispersion for5min,10min,15min,30min,45min,1h,1.5h,2h,3h,4h,6h,12h,24h. then according to the C-t curve date,we ues the Phoenix WinNonlin software to calculate the pharmacokinetic parameters,data analysis and its relative bioavailability(F):F=AUCTHC solid dispersion/AUCTHC×100%.Result:According to the methodological research,THC has a good linear relationship over the range of9.06-972.00μg·L-1, The method had a lower limit of quantitation (LLOQ) is2.00μg·L-1,the lowest detection limit is0.7μg·L-1.Extraction of THC was consistent and reproducible as indicated by a low coefficient of variation. The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. For example,compared with THC,the MRT and t1/2of THC-solid dispersion are slightly longer, the Tmax was significantly shortend, and AUCo-24h,AUC0-∞, Cmax were significantly improved, and its relative bioavailability was1.34times of THC’s. in beagles,the MRT and T1/2of THC-solid dispersion are shorter when compared with THC, the Tmax was significantly shortend,and AUCo-24h,AUC0-∞, Cmax were significantly improved, and its relative bioavailability was2.15times of THC’s. In the same dose,the volume of distribution (V/F), the area under the peak concentration (Cmax) and curve (AUC0-∞were significantly different (P<0.001) between THC and THC-solid dispersion.Conclusion:HPLC-MS/MS detection method established in this study are applicable to detecte the concentration of THC in mouse plasma and dog plasma, it is a simple, reliable, good stability and high recovery rate which suitable for pharmacokinetic study of THC, after make THC into solid dispersion,its lipid solubility was increased, the bioavailability of THC-solid dispersion in mice and dogs could significantly improve when compared with THC, achieved the expected purpose of this experiment.