他克莫司在自发性2型糖尿病小鼠体内血药浓度研究OA

Objective To investigate the tacrolimus concentrations in spontaneous type 2 diabetic db/db mice plasma.Methods Eighteen db/db mice were allocated to the db/db group,and eighteen db/m mice with an identical genetic back-ground were assigned to the db/m group.Both groups received intragastric administration of tacrolimus(10 mg·kg-1,twice dai-ly)for three consecutive days.Tacrolimus concentrations in whole blood were measured at 2 hours(C2 h),4 hours(C4 h),and 12 hours(C12h).The protein expression levels of CYP3A11 in the liver and jejunum of both groups were compared using Western blot analysis.Results Compared with the db/m group,the fasting blood glucose levels and the area under the glucose tolerance curve in the db/db group mice were significantly elevated(P<0.01).Additionally,the fasting plasma insulin(INS),glucagon-like peptide-1(GLP-1),and peptide tyrosine tyrosine(PYY)levels were markedly reduced(P<0.05).Hematoxylin and eosin(HE)staining revealed a decreased number of islet cells and the presence of numerous cytoplasmic vacuoles.Insulin immunohis-tochemical analysis demonstrated a significant reduction in insulin staining intensity(P<0.01).Furthermore,compared with the db/m group,tacrolimus concentrations in the db/db group mice at C2 h and C4 h were significantly higher(P<0.05),increasing by 2.19-fold and 0.47-fold,respectively,while the area under the blood concentration-time curve increased 0.98-fold.The expression of CYP3A11 protein in the liver and jejunum of the db/db group mice was substantially lower than that in the db/m group(P<0.05),decreasing by 32.12％and 38.50％,respectively.Conclusions The exposure of tacrolimus was found to increase in spontaneously type 2 diabetic mice(db/db mice),while the metabolic rate decreased.This phenomenon may be attributed to the reduced expression of CYP3A11 protein observed in db/db mice.