CORTISOL PHARMACODYNAMIC RESPONSE TO LONG-TERM METHYLPREDNISOLONE IN RENAL-TRANSPLANT RECIPIENTS

Study Objective. To examine the pharmacodynamic patterns of cortisol and pharmacokinetic values of long-term methylprednisolone in renal transplant recipients. Design. Twenty-four-hour pharmacokinetic and pharmacodynamic evaluation of patients who participated in a glucocorticoid-monitoring program. Setting. University-based renal transplant clinic. Patients. Fourteen renal transplant recipients studied during a clinically stable period. Interventions. The daily oral methylprednisolone dose for each patient was administered intravenously, and serial plasma cortisol and methylprednisolone samples were obtained over 24 hours. Measurements and Main Results. Methylprednisolone was analyzed by highperformance liquid chromatography. The baseline morning cortisol serum concentrations ranged from 9.8-210.7 ng/ml. After the drug was administered, cortisol. declined in a linear fashion with a mean suppression half-life of 2.4+/-0.9 hours. The cortisol nadir was reached at 12-16 hours in 11 of 14 patients. The return cortisol area under the curve (AUC-C-ret) was noted in all patients and ranged from 57-987 ng.hr/ml. The total cortisol area under the curve was greater in patients who had been transplanted for longer than 2 years (1676+/-252 vs 836+/-405 ng.hr/ml; p<0.05) compared with more recently transplanted patients. Methylprednisolone clearance ranged from 100-1181 ml/hr/kg with a mean volume of distribution of 1.3+/-0.6 L/kg. The methylprednisolone half-life ranged from 1.2-4.7 hours. The correlation between AUC-C-ret and methylprednisolone AUC was -0.64 (p<0.05). Conclusions. The pharmacodynamic response of cortisol in renal transplant recipients may be associated in part with long-term steroid exposure. However, the interrelationship between the endocrine and immune system may also affect cortisol's disposition and subsequent recovery patterns in this population. Considerable interpatient variability was apparent in both the cortisol pharmacodynamic response as well as the pharmacokinetics of methylprednisolone. These findings suggest a more individualized dosing method may be necessary to optimize the immunosuppressive effect of glucocorticoids and minimize clinical toxicity