Citrus grandis peel increases the bioavailability of cyclosporine and tacrolimus, two important immunosuppressants, in rats.

Citrus grandis peel (CGP) is a beverage ingredient and a medicinal herb in Oriental countries. Cyclosporine and tacrolimus, important immunosuppressants with narrow therapeutic windows, are widely used in transplant patients. This study investigated the effects of co-administering CGP on the bioavailability of cyclosporine and tacrolimus. Male Sprague-Dawley rats were orally administered tacrolimus or cyclosporine with and without CGP. The concentrations of cyclosporine and tacrolimus in blood were assayed by monoclonal fluorescence polarization immunoassay and microparticle enzyme immunoassay, respectively. P-glycoprotein- and cytochrome P 450 3A4 (CYP3A4)-associated mechanisms were investigated by using everted rat intestinal sac and recombinant CYP3A4 isozyme. The results showed that CGP significantly increased the bioavailability of cyclosporine and tacrolimus by 100.0% and 234.7%, respectively. Ex vivo studies indicated that the interaction was mediated by the inhibition of CYP3A4. We suggest that CGP is contraindicated for transplant patients treated with cyclosporine or tacrolimus to minimize the risk of intoxication.