PHARMACOKINETICS OF ORALLY AND INTRAVENOUSLY ADMINISTERED CYCLOSPORINE IN PRE-KIDNEY TRANSPLANT PATIENTS

The pharmacokinetics of cyclosporine (CSA) and four metabolites were e valuated in eight hemodialysis subjects awaiting renal transplantation to compare metabolic patterns with those observed in post-transplant patients and normal volunteers. Each subject received a single 4-mg/kg intravenous and a single 10-mg/kg oral dose separated by a 1-week was hout period. Blood samples were collected before and at .5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 24 hours after CSA dosing. Cyclospor ine blood, plasma, and metabolite (M17, M1, M18, M21) levels were dete rmined by high-pressure liquid chromatography. Mean (+/- standard devi ation) CSA blood clearance was .47 +/- .15 L/hour/kg, steady-state vol ume of distribution (V-ss) was 1.9 +/- .5 L/kg, and mean residence tim e (MRT) was 4.4 +/- 1.8 hours after intravenous dosing. With plasma, m ean clearance was .70 +/- .31 L/hour/kg, V-ss was 2.4 +/- 1.2 L/kg, an d MRT was 3.7 +/- 2.2 hours. Cyclosporine bioavailability (F) averaged 24 +/- 11 and 24 +/- 15%, using blood and plasma, respectively. Value s for clearance and V-ss were approximately 30 to 100% greater than co mparable estimates in healthy volunteers, but F and MRT were not alter ed to this extent. These changes might be explained on the basis of de creased protein binding in uremic patients. The area under the curve r atio for M17 and M1 to CSA increased an average of 1.7- and 3.9-fold, respectively, after oral dosing compared with intravenous administrati on, indicating increased conversion during first-pass metabolism.