Pharmacokinetics of Orally and Intravenously Administered Cyclosporine in Pre—Kidney Transplant Patients

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Abstract
The pharmacokinetics of cyclosporine (CSA) and four metabolites were evaluated 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 washout 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. Cyclosporine blood, plasma, and metabolite (M17, M1, M18, M21) levels were determined by high‐pressure liquid chromatography. Mean (±standard deviation) CSA blood clearance was .47 ± .15 L/hour/kg, steady‐state volume of distribution (Vss) was 1.9 ± .5 L/kg, and mean residence time (MRT) was 4.4 ± 1.8 hours after intravenous dosing. With plasma, mean clearance was .70 ± .31 L/hour/kg, Vss was 2.4 ±1.2 L/kg, and MRT was 3.7 ± 2.2 hours. Cyclosporine bioavailability (F) averaged 24 ± 11 and 24 ± 15%, using blood and plasma, respectively. Values for clearance and Vss were approximately 30 to 100% greater than comparable estimates in healthy volunteers, but F and MRT were not altered to this extent. These changes might be explained on the basis of decreased protein binding in uremic patients. The area under the curve ratio for M17 and M1 to CSA increased an average of 1.7‐ and 3.9‐fold, respectively, after oral dosing compared with intravenous administration, indicating increased conversion during first‐pass metabolism.