The pharmacokinetics of cyclosporine were studied in the blood of five normal healthy volunteers (two men and three women) after each received oral and intravenous cyclosporine alone and with concomitant oral ketoconazole. Administration of ketoconazole caused a significant decrease in intravenous cyclosporine clearance (0.18 +/- 0.05 L/kg/hr versus 0.32 +/- 0.09 L/hr/kg) and a significant increase in cyclosporine oral bioavailability (56.4% +/- 11.7% versus 22.4% +/- 4.8%) compared with values before ketoconazole administration. Steady-state volume of distribution for intravenously administered cyclosporine was unchanged (1.26 +/- 0.44 L/kg versus 1.10 +/- 0.27 L/kg). Hepatic bioavailability (1 - hepatic extraction ratio) calculated for intravenous cyclosporine increased by 11% in the presence of ketoconazole (86.3% +/- 3.7% versus 75.2% +/- 6.6% without ketoconazole), which accounts for only one third of the observed increase in cyclosporine oral bioavailability. Because it is unlikely that ketoconazole had a significant effect on either cyclosporine absorption or hepatic blood flow, the increase in cyclosporine bioavailability observed in this study is most likely explained by inhibition of gastrointestinal cytochrome P450 enzymes.