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

Study Objective. To examine the pharmacodynamic patterns of cortisol a nd pharmacokinetic values of long-term methylprednisolone in renal tra nsplant recipients. Design. Twenty-four-hour pharmacokinetic and pharm acodynamic evaluation of patients who participated in a glucocorticoid -monitoring program. Setting. University-based renal transplant clinic . Patients. Fourteen renal transplant recipients studied during a clin ically stable period. Interventions. The daily oral methylprednisolone dose for each patient was administered intravenously, and serial plas ma cortisol and methylprednisolone samples were obtained over 24 hours . Measurements and Main Results. Methylprednisolone was analyzed by hi ghperformance liquid chromatography. The baseline morning cortisol ser um concentrations ranged from 9.8-210.7 ng/ml. After the drug was admi nistered, cortisol. declined in a linear fashion with a mean suppressi on 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 curv e (AUC-C-ret) was noted in all patients and ranged from 57-987 ng.hr/m l. The total cortisol area under the curve was greater in patients who had been transplanted for longer than 2 years (1676+/-252 vs 836+/-40 5 ng.hr/ml; p<0.05) compared with more recently transplanted patients. Methylprednisolone clearance ranged from 100-1181 ml/hr/kg with a mea n volume of distribution of 1.3+/-0.6 L/kg. The methylprednisolone hal f-life ranged from 1.2-4.7 hours. The correlation between AUC-C-ret an d methylprednisolone AUC was -0.64 (p<0.05). Conclusions. The pharmaco dynamic response of cortisol in renal transplant recipients may be ass ociated in part with long-term steroid exposure. However, the interrel ationship between the endocrine and immune system may also affect cort isol's disposition and subsequent recovery patterns in this population . Considerable interpatient variability was apparent in both the corti sol pharmacodynamic response as well as the pharmacokinetics of methyl prednisolone. These findings suggest a more individualized dosing meth od may be necessary to optimize the immunosuppressive effect of glucoc orticoids and minimize clinical toxicity