Role of Prednisolone Pharmacokinetics in Postchallenge Glycemia After Renal Transplantation

Abstract

Prednisolone may cause hyperglycemia after organ transplantation. Even at comparable weight-adjusted doses, prednisolone side effects vary considerably between individuals, suggesting between-patient pharmacokinetic differences. In renal transplant patients, assessment of glucocorticoid diabetogenicity is confounded by calcineurin inhibitors (CNIs). The present study aimed to investigate, in a CNI-free setting, the association between exposure to unbound prednisolone and glucose tolerance in stable nondiabetic long-term renal transplant patients. An oral glucose tolerance test and a 12-hour prednisolone pharmacokinetic study were performed in 108 nondiabetic CNI-naive subjects (41 women and 67 men) treated with prednisolone (median 0.15 mg kg d, interquartile range 0.14-0.18 mg kg d) and azathioprine. The area under the curve (AUC) of unbound prednisolone was analyzed in multiple linear regression analysis with 120-minute postchallenge glucose AUC as the dependent variable. A high AUC of unbound serum prednisolone was independently associated with a high glucose AUC (P = 0.030). A high glucose AUC was also associated with a high patient age and triglyceride level (both P < or = 0.001). No correlation was observed between the daily prednisolone dosage (mg/d or mg kg d) and glucose AUC. The association between exposure to unbound prednisolone and postchallenge glycemia is in line with current knowledge about mechanisms behind steroid-related side effects but has not previously been documented. The result may argue in favor of measuring unbound prednisolone in clinical settings. Increasing exposure to unbound prednisolone was independently associated with postchallenge glycemia. No such relationship was observed for prednisolone daily dose per se.