DISPOSITION OF INTRAVENOUS AND ORAL CYCLOSPORINE AFTER ADMINISTRATIONWITH GRAPEFRUIT JUICE

Objective: To examine the effect of grapefruit juice on the dispositio n of cyclosporine after administration of oral and intravenous doses t o healthy male subjects. Methods: Subjects received two oral doses of cyclosporine (7.5 mg/kg) and two intravenous doses (2.5 mg/kg infused for 3 hours), with each dose separated by a 1-week washout period. Gra pefruit juice (250 mi) was ingested immediately before one oral and on e intravenous dose and again 2 hours later. Blood samples were collect ed for a 24-hour period, and whole blood concentrations of cyclosporin e were measured with use of a specific monoclonal radioimmunoassay. Re sults: Grapefruit juice had no effect on any pharmacokinetic parameter when given with intravenous cyclosporine. After oral administration, grapefruit juice significantly increased peak concentration (936 versu s 1340 ng/ml), as well as area under the curve (6722 versus 10,730 ng . hr/ml) but had no effect on elimination half-life. Absolute bioavail ability of cyclosporine was increased from 0.22 to 0.36 (average incre ase, 62%) by grapefruit juice. Conclusions: The lack of effect on syst emic clearance after intravenous cyclosporine suggests that grapefruit juice improves oral bioavailability by increasing absorption or reduc ing gut wall metabolism. The latter is more likely in view of studies that suggest significant gut wall metabolism of cyclosporine by CYP3A enzymes known to be inhibited by components of grapefruit juice.