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Pharmacokinetics and Pharmacodynamic Response of Methylprednisolone in Premenopausal Renal Transplant Recipients

From the Departments of Pharmacy Practice and Medicine, Schools of Pharmacy and Pharmaceutical Sciences and Medicine and Biomedical Sciences, University at Buffalo, and the Renal Division, Erie County Medical Center, Buffalo, New York.

Chronic glucocorticoid therapy is prescribed in renal transplant recipients according to empiric dose-tapering schedules, which assume a similar pharmacologic response in men and women. The study objectives were (a) to compare the pharmacokinetics of methylprednisolone in premenopausal renal transplant recipients with previously studied male counterparts and (b) to describe the pharmacodynamic response of the hypothalamic-pituitary-adrenal axis during chronic steroid therapy. Thirteen stable premenopausal subjects (ages 30 to 49 years) receiving chronic glucocorticoid therapy were evaluated for methylprednisolone, cortisol, and adrenocorticotropin hormone (ACTH) over 24 hours after an intravenous infusion of methylprednisolone sodium succinate. Most patients were evaluated during the luteal phase of the menstrual cycle. Pharmacokinetic parameters of methylprednisolone with cortisol and ACTH responses were determined. Results were compared to counterpart male subjects who participated in a prior study. The total clearance of methylprednisolone for the female subjects was 15.6 ± 5.99 L/h compared to the males with 21.5 ± 8.67 L/h (P < .05). When normalized for total or lean body weight, no significant difference was noted (P = .614). A 3-fold interpatient variation in weight-adjusted clearance was noted for female subjects. Dose-normalized methylprednisolone a AUC was greater in women (66.1 ± 19.8 ng•h/mL) than men (46.4 ± 19.7 ng•h/mL) (P = .174). Total cortisol AUC was not different between groups (P = .599). Despite chronic steroid therapy, 9 of 13 women had a normal cortisol profile and an ACTH AUC of 299 ± 102 pg•h/mL. It was concluded that methylprednisolone clearance in women was significantly slower compared to men. When drug clearance was normalized for total and lean body weight, no gender difference was noted. These findings are in contrast to prior data indicating a more rapid methylprednisolone clearance in healthy women. These findings suggest that doses of glucocorticoids should be prescribed on a milligram/kilogram basis instead of empiric dosing schedules.

Key Words: Glucocorticoids • hypothalamic-pituitary-adrenal axis • methylprednisolone • pharmacokinetics • pharmacodynamics • adrenocorticotropin hormone

Address for reprints: Kathleen M. Tornatore, PharmD, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 319 Cooke Hall, Buffalo, NY 14260-1200.

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