Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability.
The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the immunosuppressive drug cyclosporine were studied in 187 patients with uremia. All patients underwent a pharmacokinetic evaluation including a 3 mg/kg intravenous dose of cyclosporine and a 14 mg/kg oral dose of cyclosporine. Cyclosporine was analyzed by specific monoclonal radioimmunoassay on whole blood samples. Statistical analysis included univariate analyses and stepwise multiple regression analysis. Major findings were as follows: The bioavailability (F) of cyclosporine was significantly lower in black patients than in white patients (mean values of 30.9% +/- 12.3% and 39.5% +/- 16.5%, respectively; p < 0.001). This difference was noted both before transplant and at 1 week after kidney transplantation, at which time the corresponding mean values were 28.6% +/- 15.5% and 36.1% +/- 15.5%, respectively (p < 0.01). Other factors that correlated with F were serum triglyceride (positively) and blood hemoglobin concentrations (inversely). Patients with diabetes displayed a longer mean absorption time than other patients and a larger volume of distribution of cyclosporine at steady state (VSS). Other factors that correlated with VSS were serum albumin concentration and patient height. Cyclosporine clearance (CL) decreased with patient age and also with increasing concentrations of serum triglycerides and blood hemoglobin. It was lower in patients with the pretransplant diagnosis of nephrosclerosis than in patients with other diseases. Several pharmacokinetic parameters correlated with the level of substances that can potentially bind cyclosporine in the blood. Serum triglycerides correlated with maximum concentration, time to maximum concentration, F, and CL. Blood hemoglobin concentration and blood hematocrit correlated with F, CL, and intravenous mean residence time. Although several relationships were observed between demographic factors and cyclosporine pharmacokinetics, the racial difference in F is of great clinical significance and may contribute to the poorer outcome observed after kidney transplantation in black patients.
Lindholm
A
A
Department of Surgery, University of Texas Medical School, Houston.
Welsh
M
M
Alton
C
C
Kahan
B D
BD
D000328:Adult; D000704:Analysis of Variance; D001682:Biological Availability; D001774:Blood Chemical Analysis; D016572:Cyclosporine / Q000493:pharmacokinetics*; D003586:Cytomegalovirus Infections / Q000378:metabolism; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D044469:Racial Groups; D012044:Regression Analysis; D014511:Uremia / Q000378:metabolism*
D016572:Cyclosporine