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

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Abstract

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant 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 relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 hr. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon fades) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206±70 ml/hr/kg) was significantly 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 distribution = 1.33±0.27 L/kg, P=0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732+443 nghr/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 hr 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 nghr/ml and 370±207 nghr/ml for white patients (P=0.28). The serum cortisol nadir for black patients was 12.3±7.2 ng/ml, which was significantly 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 facies and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 of 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had higher cortisol AUCs with lower methylprednisolone clearances than the white group.

The slower methylprednisolone clearance (resulting in increased drug exposure) and the defined cortisol daily patterns present in black patients could help to explain the different toxicity profiles seen in these two groups. These findings suggest that the traditional use of fixed-dose protocols may not be an optimal method for prescribing methylprednisolone immunosuppression in both black and white renal transplant recipients.

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