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In order to minimize chronic adverse effects, the use of the lowest effective doses of corticosteroids (prednisone or methylprednisolone-MEPN) are currently recommended in the combination immunosuppressive protocols prescribed in RTR. Therefore, more RTR are receiving steroid-sparing therapy that employ every other day (QOD) glucocorticoid regimens based upon empiric dosing titration. To examine total glucocorticoid exposure during QOD dosing, seven (4 males; 3 females) stable RTR (ranging from 7 months to 7 years post-transplant) stabilized on QOD glucocorticoid doses were evaluated. Patients (mean serum creatinine: 1.4 + 0.2 mg/dl) were administered their respective oral MEPN dose (dose range: 4 to 14 mg QOD) by intravenous infusion at 8 AM of study. Blood samples were collected at time 0 (0800) and for 24 hours following and analyzed with HPLC for MEPN and cortisol. Significant interpatient variability was noted in the clearance (CL) of MEPN that ranged from 180 to 574 ml/hr/kg. The corresponding half-life (t12) ranged from 2.0 to 3.7 h. A defined 24 h cortisol profile was noted an all patients. Cortisol concentrations (mean cortisol at time 0:127 + 50 ng/ml) declined concurrent with the serum MEPN. Cortisol rebounded from a mean nadir concentration of 9.2 + 4.4 ng/ml to 24 hour mean cortisol concentration of 104 + 39 ng/ml. The total ng/ml AUC ranged from 541 to 1438 ng*h/ml and was not correlated with dose or CL of MEPN. No significant correlation was noted between these pharmacologic parameters aid patient demographics. These results indicate that pronounced interpatient variability in the pharmacokinetics of MEPN exists during QOD therapy. In addition, the cortisol response during QOD therapy suggests unpredictable recovery rates of the HPA axis. The variation in total glucocorticoid exposure during empiric tapering to QOD therapy suggest that a more objective approach is needed to maintain adequate immunosuppression while attempting to avoid chronic steroid toxicity. These variations in the MEPN clearance and cortisol recovery may explain why aggressive steroid tapering is complicated by rejection episodes that occur in an unpredictable manner.