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Objective To examine the changes of diabetic rats skin and the effects on the percutaneous absorption of ketoconazole.Methods Diabetes mellitus (DM) rat model was prepared with the method of streptozocin intraperitoneal injection.After injection ,rats abdominal skins of different DM periods were made for HE stained tissue slices to find if any histological changes occured.Abdominal skin was cut to carry out an in-vitro penetration experiment on an improved Franz diffusion cells four weeks after treptozocin intraperitoneal injection,and then the permeation rates of control group and DM group can be calculated.In vivo study, the concentrations of KTZ in blood and abdominal subcutaneous were monitored by microdiaylsis after KTZ gelatin/cream/ointment was applied on rats skin respectively, and then the subcutaneous tissue/plasma drug concentrationtime profiles and various kinetic parameters were analysed.Results The tissue slices showed that little change was observed in one-week DM rats skin, but one-month DM rats skin was observed thinner, and it became much thinner when rats were two-month diabetes.After making a rat into diabetic, the rats skin goes through a pathological change.The permeation rates of KTZ gelatin -control group and KTZ gelatin-DM group were 3.38±0.36 and 4.56±0.67μg·h-1·cm-2, respectively; the permeation rates of KTZ cream-control group and KTZ cream-DM group were 1.33±0.41 and 1.87±0.11μg·h-1·cm-2, respectively; the permeation rates of KTZ ointment -control group and KTZ ointment-DM group were 0.77±-0.42 and 1.72±0.86μg·h-1·cm-2, respectively.There was significant difference between the control and the DM group (P<0.05).The results of in-vivo microdialysis showed that subcutaneous drug concentrations in diabetic rats were significantly higher than normal rats, the maximum concentration (Cmax) and area under curve (AUCall) compared with the normal group were statistical significant at P<0.05, indicating that there surely be changes in the skin of diabetic rats and increase the topical drug absorption.However, in the consequence of blood microdialysis, the two groups were not significant difference.Conclusion Diabetes induce some skin pathological changes, which may result in the increasing permeation of KTZ.Therefore, in order to reduce drug side effects and improve the diabetics quality of life, it is necessary to adjust the dose while KTZ or some other topical preparations were applied on the skin in case of diabetes mellitus.