The pharmacokinetics of oral and intravenous prednisolone and intravenous erythromycin were examined in premenopausal women, postmenopausal women not undergoing hormone replacement therapy, postmenopausal women undergoing estrogen replacement therapy, and postmenopausal women undergoing estrogen and progestin replacement therapy. The unbound clearance of prednisolone was significantly lower in postmenopausal women (11.6 +/- 2.3 ml/min/kg) than in premenopausal women (16.6 +/- 3.5 ml/min/kg). A comparable difference was also observed in total clearance and in half-life. The bioavailability and volume of distribution of prednisolone were unaffected by menopausal status. Hormone replacement therapies did not significantly affect prednisolone pharmacokinetics. In contrast to prednisolone elimination, erythromycin elimination, as measured by the erythromycin breath test, was not significantly affected by either menopausal status or hormone replacement therapy. In addition, there was no correlation between prednisolone clearance and the erythromycin breath test result. Although cytochrome P450 3A4 (CYP3A4) has been implicated in steroid hormone metabolism, these results suggest that another enzyme system, which is decreased in menopause (rather than simply an age effect), is also involved in prednisolone metabolism.