Disposition of intravenous and oral cyclosporine after administration with grapefruit juice

To examine the effect of grapefruit juice on the disposition of cyclosporine after administration of oral and intravenous doses to healthy male subjects.

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. Grapefruit juice (250 ml) was ingested immediately before one oral and one intravenous dose and again 2 hours later. Blood samples were collected for a 24-hour period, and whole blood concentrations of cyclosporine were measured with use of a specific monoclonal radioimmunoassay.

Grapefruit juice had no effect on any pharmacokinetic parameter when given with intravenous cyclosporine. After oral administration, grapefruit juice significantly increased peak concentration (936 versus 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 bioavailability of cyclosporine was increased from 0.22 to 0.36 (average increase, 62%) by grapefruit juice.

The lack of effect on systemic clearance after intravenous cyclosporine suggests that grapefruit juice improves oral bioavailability by increasing absorption or reducing 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.