Sequential changes in the pharmacokinetics of cyclosporine (CsA) and metabolites Ml, M17, and M21 were determined, 1, 3, and 12 weeks after initiation of CsA therapy in 21 renal transplant recipients. Concentrations of CsA and its metabolites were measured by HPLC. The dose-adjusted AUC (AUCτSS) and 24-hour trough (Ctrough24) level of CsA and the metabolites increased significantly during the study period. However, there was no change in the AUCπSS ratio of each of the metabolites to that of CsA, suggesting that CsA metabolism did not change. However, the factors that alter the binding and distribution of CsA (i.e., hematocrit, plasma proteins, and lipoproteins) showed a significant rise during the study period, and the rise correlated well with the observed changes in AUCπSS and Ctrough24·. Thus alterations in the distribution and binding of CsA and its metabolites in blood, rather than reduction in the metabolism of CsA, may explain changes in CsA pharmacokinetics over time.