Calcineurin inhibitors, typical immunosuppressive agents, are used for medical treatment of the steroid-refractory ulcerative colitis inflammatory bowel disease (IBD). Increased brain transport of the calcineurin inhibitor cyclosporin A elevates the risk for the occurrence of neurotoxic adverse effects including tremors under the pathological conditions such as partial hepatectomy. However, it has not been well known whether IBD regulates the blood-brain barrier (BBB) permeability for calcineurin inhibitors. Here, we used C57BL/6 mice treated with 3.5 % sodium dextran sulfate (DSS) for 12 days as an IBD model to evaluate brain uptake of the cyclosporin A and tacrolimus using an in situ transcardial perfusion technique. [³H]-Cyclosporin A and [³H]-tacrolimus uptake in the brain of DSS mice were significantly decreased. The increased expression levels of the P-glycoprotein were observed in brain microvasculatures of the DSS mice, suggesting that P-glycoprotein functions may be up-regulated in DSS mice. These findings demonstrate that IBD model mice exhibit decreased transport of the calcineurin inhibitors across BBB by up-regulating P -glycoprotein activity. Thus, IBD may not be included in the risk factors for the neurotoxic adverse effects of calcineurin inhibitors.