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Pharmacokinetics of Orally and Intravenously Administered Cyclosporine in Pre—Kidney Transplant Patients
Author(s) -
Aweeka Francesco T.,
Tomlanovich Stephen J.,
Prueksaritat Thomayant,
Gupta Suneel K.,
Benet Leslie Z.
Publication year - 1994
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1994.tb03967.x
Subject(s) - pharmacokinetics , volume of distribution , dosing , medicine , bioavailability , metabolite , hemodialysis , urology , transplantation , ciclosporin , oral administration , pharmacology , anesthesia
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 (V ss ) 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, V ss 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 V ss 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.