Reed K

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 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 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) 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 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 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 ng.hr/ml and 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 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Racial differences in the pharmacokinetics of methylprednisolone in black and white renal transplant recipients

Study Objective. To examine the comparative pharmacokinetics of long‐term methylprednisolone therapy in black and white renal transplant recipients.

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.

Repeated Assessment of Methylprednisolone Pharmacokinetics During Chronic Immunosuppression in Renal Transplant Recipients

Objective: To compare the pharmacokinetics of methylprednisolone in renal transplant recipients on 2 occasions separated by at least 1 month during chronic immunosuppression. Design: A prospective unblinded trial. Patients: Ten renal transplant recipients (aged 25–62 years) evaluated in a public university-affiliated hospital clinic. Interventions: All patients received their chronic oral dose of methylprednisolone as a 10–20-minute intravenous infusion during the 2 study periods. Main Outcome Measures: Serum methylprednisolone concentrations were determined by HPLC and were used to generate the pharmacokinetic parameters of the drug. Results: During study 1, which ranged from 1.2 to 24 months posttransplant, the mean ± SD methylprednisolone dose was 13.2 ± 6.4 mg. In study 2 (2.5–38,5 mo posttransplant), the mean dose was 10.6 ± 3 mg. During both study periods, methylprednisolone concentrations exhibited a monoexponential decline. Considerable variability in methylprednisolone clearance was observed between periods in certain patients. Four of the 10 patients demonstrated a reduction in clearance from study 1 to study 2, which ranged from a 28% to a 53% decrease. Two patients exhibited an increase in clearance of 40% and 49%. The mean ± SD total body clearance in study I was 363 ± 330 mL/min/kg, whereas the mean volume of distribution was 1.18 ± 0.53 L/kg. The mean elimination rate constant was 0.29 ± 0.14 h−1, with a mean serum half-life of 2.87 ± 1.15 h during the first phase. In study 2, the mean methylprednisolone clearance was 261 ± 150 mL/min/kg (p > 0.05) and the mean volume of distribution was 0.89 ± 0.31 L/kg (p > 0.05). The mean serum half-life of methylprednisolone was 2.91 ± 0.60 h (p > 0.05), with the mean elimination rate constant of 0.25 ± 0.06 h−1(p > 0.05). Conclusions: These data demonstrate that intrapatient variability in methylprednisolone clearance exists among certain renal allograft recipients. As a result of the observed variability, patients who are continued on the same dose of methylprednisolone during the posttransplant period of chronic immunosuppression will be subjected to a changing pattern of exogenous glucocorticoid exposure. The impact of these changing patterns requires further prospective evaluation.