[Pharmacokinetics of cyclosporine and its metabolites in patients undergoing kidney transplantation].
Pharmacokinetics of cyclosporine shows high inter and intra-individual variability and changes in several parameters are often found after kidney transplantation. PURPOSE--Evaluate serial studies of the pharmacokinetics of cyclosporine and its metabolites in patients undergoing kidney transplantation. METHODS--The pharmacokinetics of cyclosporine and its metabolites were analyzed in 70 studies performed in 29 patients, 26 before and 44 after kidney transplantation. The blood cyclosporine concentration was determined in 17 samples obtained after is oral or intravenous administration, using radioimmunoassay with specific (RIE-MoSP) and nonspecific (RIE-MoNP) monoclonal antibodies. RESULTS--The values of area-under-the-time-concentration curve (AUC), bioavailability (F), peak concentration (Cmax) and the 12 and 24 trough levels (C12 and C24), determined with RIE-MoSP, were lower than that obtained with RIE-MoNP, and the clearance (CL) and the volume of distribution (Vd) were higher. The elimination half-lives (t1/2) for both methods were not different. The absorption followed a zero order kinetic, demonstrating an inverse correlation between cyclosporine dose (mg/kg) and AUC/dose (r = -0.55, RIE-MoSP and r = -0.42, RIE-MoNP). Bioavailability ranged between 18% and 68% (RIE-MoSP) and were overestimated when calculated using RIE-MoNP (38% to 100%) owing to extensive cyclosporine metabolization during the first passage through the intestine and the liver. The metabolic rate analyzed by the ratio of blood concentrations determined with RIE-MoNP and RIE-MoSP (NP/SP), increased during the first 12 hours after cyclosporine administration, and was higher after oral dosing. The hematocrit and the serum lipoproteins concentrations significantly correlated with several pharmacokinetics parameters, mainly when they were determined with RIE-MoSP. The correlation between one sample obtained at any time after cyclosporine administration and the AUC were unsatisfactory, even the trough levels of 12 and 24 hours. AUCs calculated with 3 selected samples chosen by multiple linear regression correlated with AUC calculated using 17 samples, with a determination coefficient higher than 0.95 (RIE-MoSP, r = 0.975; RIE-MoNP, r = 0.974). CONCLUSION--Among all the parameters calculated, parameters of total exposure to the drug (AUC, AUC/dose, Cssav) showed the best correlation with the dose of cyclosporine, hematocrit and serum lipoproteins concentration. The methodology simplification, reducing the number of samples to calculate AUC, could be a good strategy to apply routinely these parameters in clinical transplantation.
Silva Junior
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HT
Disciplina de Nefrologia da Escola Paulista de Medicina, São Paulo.
Pereira
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AB
Ajzen
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Bueno
V
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Pestana
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JO
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000032:analysis; D016572:Cyclosporine / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay
D000911:Antibodies, Monoclonal; D016572:Cyclosporine
Farmacocinética da ciclosporina e de seus metabólitos em pacientes submetidos a transplante renal.