THE EFFECTS OF KETOCONAZOLE ON THE INTESTINAL METABOLISM AND BIOAVAILABILITY OF CYCLOSPORINE

The pharmacokinetics of cyclosporine were studied in the blood of five normal healthy volunteers (two men and three women) after each receiv ed oral and intravenous cyclosporine alone and with concomitant oral k etoconazole, Administration of ketoconazole caused a significant decre ase in intravenous cyclosporine clearance (0.18 +/- 0.05 L/kg/hr versu s 0.32 +/- 0.09 L/hr/kg) and a significant increase in cyclosporine or al bioavailability (56.4% +/- 11.7% versus 22.4% +/- 4.8%) compared wi th values before ketoconazole administration. Steady-state volume of d istribution for intravenously administered cyclosporine was unchanged (1.26 +/- 0.44 L/kg versus 1.10 +/- 0.27 L/kg), Hepatic bioavailabilit y (1 - hepatic extraction ratio) calculated for intravenous cyclospori ne increased by 11% in the presence of ketoconazole (86.3% +/- 3.7% ve rsus 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 e ither cyclosporine absorption or hepatic blood flow, the increase in c yclosporine bioavailability observed in this study is most likely expl ained by inhibition of gastrointestinal cytochrome P450 enzymes.