UPLC-MS/MS测定比格犬血浆中双氢青蒿素的浓度及其药代动力学研究OA

Dihydroartemisinin,a derivative of artemisinin,exhibits antimalarial,antitumour,antiviral,anti-inflammatory,immunomodulatory,antiparasitic,antifibrotic,and antihypertensive pharmacological activities.To investigate pharmacokinetics,oral bioavailability,and dose-exposure relationship of dihydroartemisinin in Beagle dogs,this study established and validated a rapid and sensitive quantitative ultra-performance liquid chromatography-mass spectrometry(UPLC-MS/MS)method for quantifying dihydroartemisinin in Beagle dog plasma.This validated method was then applied to the pharmacokinetic study of Beagle dog plasma after intravenous injection of a single dose of dihydroartemisinin and after gavage administration of different doses of dihydroartemisinin,to clarify the absolute bioavailability of dihydroartemisinin after gavage administration to Beagle dogs and to investigate the relationship between the different doses of dihydroartemisinin and its exposure(Cmax,AUC0-t)in Beagle dogs.The results revealed that the specificity,linearity,accuracy,precision,stability,and matrix effect of this method met the requirements for the determination of biological samples.Rapid elimination of dihydroartemisinin was observed in Beagle dogs following intravenous administration of dihydroartemisinin.The half-life(t1/2)of dihydroartemisinin in the plasma after intravenous injection was 0.37 h for females and 0.35 h for males.The area under the curve(AUC0-t)for dihydroartemisinin was 395 ng·h·mL-1 for females and 428 ng·h·mL-1 for males.The mean residence time(MRT0-t)was 0.73 h for females and 0.6 h for males.The clearance rate(CL)was 3.12 L·h-1·kg-1 for females and 2.91 L·h-1·kg-1 for males.Following gavage administration of dihydroartemisinin,concentrations of the drug peaked rapidly in dog plasma,all between 0.08 and 0.25 h.The absolute bioavailability was 0.46%for males and females at a dose of 1.2 mg·kg-1,0.55%and 1.07%at 2.4 mg·kg-1,and 0.29%and 0.37%at 9.6 mg·kg-1,respectively.This established UPLC-MS/MS method for dihydroartemisinin in plasma exhibited good specificity and sensitivity.Dihydroartemisinin was metabolized very rapidly in dogs with low oral bioavailability,and the exposure levels(Cmax,AUC0-t)increased with doses(1.2-9.6 mg·kg-1)but showed a non-linear correlation.