This study was conducted to determine the effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its major metabolites, M1 and M17, in 12 healthy volunteers. Each subject received two oral doses of microemulsion cyclosporine with water or grapefruit juice. Each subject also received intravenous cyclosporine on a separate occasion. Blood samples were collected for assay of cyclosporine, M1, and M17 during a 24-hour period, and were analyzed by a high-performance liquid chromatography method. Compared with water, administration with grapefruit juice significantly increased peak concentration (Cmax) and area under the concentration-time (AUC) of cyclosporine. Administration with grapefruit juice increased the absolute bioavailability of microemulsion cyclosporine by 45%. For cyclosporine metabolites, administration with grapefruit juice decreased the Cmax and AUC of M1 by 21% and 15%, respectively. These findings suggest that concurrent administration with grapefruit juice increases the bioavailability of microemulsion cyclosporine significantly compared with water in healthy volunteers. The grapefruit juice affects each metabolite formation and its pharmacokinetics differently, which suggests that the major site of its formation is different.