METHYLPREDNISOLONE PHARMACOKINETICS, CORTISOL RESPONSE, AND ADVERSE-EFFECTS IN BLACK-AND-WHITE RENAL-TRANSPLANT RECIPIENTS

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal tr ansplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relations hip of glucocorticoid metabolism to steroid-induced adverse effects am ong specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were e nrolled. All patients had stable renal function and were matched for a ge, weight, and time since transplant. Standard pharmacokinetic parame ters for methylprednisolone were determined and cortisol responses wer e characterized by total cortisol area under the concentration curve ( AUC), return cortisol AUC, and cortisol suppression half-life. All pat ients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infus ion with serial plasma samples obtained over 24 hr. The patients were assessed for the presence of specific cushingoid manifestations (buffa lo hump, moon facies) and steroid-associated diabetes. Methylprednisol one and cortisol were analyzed via HPLC. In the black patients, the me an clearance of methylprednisolone (206+/-70 ml/hr/kg) was significant ly slower with a smaller volume of distribution (0.95-0,32 L/kg) when compared with the white group (327+/-129 ml/hr/kg, P=0.03; volume of d istribution = 1.33+/-0.27 L/kg, P=0.015). Despite chronic methylpredni solone therapy, a definite 24-hr cortisol response pattern was noted i n 15 of the 18 patients with a mean total cortisol AUC of 732+/-443 ng . hr/ml in blacks and 539 +/- 361 ng . hr/ml in whites (P=0,17, black vs. white). The mean cortisol suppression half-life was 4.31+/-1.54 h r in black recipients and 4.11+/-1.49 hr in whites (P=0.48). The mean return cortisol AUC for the black patients was 327+/-279 ng . hr/ml an d 370+/-207 ng . hr/ml for white patients (P=0.28). The serum cortisol nadir for black patients was 12.3+/-7.2 ng/ml, which was significantl y higher than the cortisol nadir in white patients (6.4+/-4.4 ng/ml; P =0.03). A majority (94%) of patients (9 black, 8 white) had moon facie s and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 o f 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had h igher cortisol AUCs with lower methylprednisolone clearances than the white group. The slower methylprednisolone clearance (resulting in inc reased drug exposure) and the defined cortisol daily patterns present in black patients could help to explain the different toxicity profile s seen in these two groups. These findings suggest that the traditiona l use of fixed dose protocols may not be an optimal method for prescri bing methylprednisolone immunosuppression in both black and white rena l transplant recipients.