Jeff Gray

Cyclosporine Kinetics in Healthy Volunteers

The pharmacokinetics of cyclosporine was studied in five healthy male volunteers following intravenous administration. The subjects received 2.1 mg/kg of cyclosporine as a two‐hour intravenous infusion. Blood samples were collected over the subsequent 48 hours. Cyclosporine was extracted from whole blood and analyzed by high‐performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Following the intravenous infusion of cyclosporine, the drug exhibited multicompartmental behavior. The harmonic mean distribution half‐life based on HPLC data was 0.45 hours, and the harmonic mean terminal disposition half‐life was 6.2 hours. The clearance of cyclosporine based on HPLC cyclosporine concentrations was 3.9 mL/min/kg, and the volume of distribution at steady state of cyclosporine was 1.23 L/kg. Cyclosporine has a shorter half‐life, lower clearance, and smaller Vss in healthy persons as compared to patient populations. The differences observed in the pharmacokinetics of cyclosporine in healthy persons as compared to patient populations may be due to differences in hematocrit, lipoprotein profiles, and/or concurrent drug therapy between the groups. Cyclosporine concentrations determined by RIA were consistently higher than those determined by HPLC, resulting in a significantly higher area under the blood concentration versus time curve and lower clearance rate for cyclosporine. We conclude that: (1) kinetic parameter estimates for cyclosporine are different in healthy individuals as compared with organ‐transplant recipients, and (2) the kinetic parameters for cyclosporine are different, depending on the assay technique used.

Antipyrine kinetics in liver disease and liver transplantation

Antipyrine kinetics were studied in seven normal subjects, 10 patients with liver disease, and 13 clinically stable patients who received a liver transplant. Five patients were studied both before and after liver transplantation. Antipyrine concentrations in saliva after oral dosing were measured by HPLC. The antipyrine t½was significantly longer (P < 0.05) in patients with liver disease than in patients undergoing liver transplantation and normal subjects. Antipyrine clearance was not significantly different between patients undergoing liver transplantation and normal subjects, but it was significantly reduced (P < 0.05) in patients with liver disease. In five patients who were studied before and after liver transplantation, there was a significant (P < 0.05) increase in the antipyrine clearance and a marked reduction in its t½after liver transplantation. These results indicate that liver transplantation improves the drug metabolizing ability of patients with liver disease and that the oxidative metabolizing capacity of the liver in clinically stable patients after liver transplantation is similar to that of normal subjects.