Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion

Abstract

The disposition of methylprednisolone was examined in six normal subjects after the injection of 20 mg iv methylprednisolone sodium succinate. Disposition studies were performed both without and with ketoconazole, 200 mg/day, for 6 days. Ketoconazole increased the methylprednisolone AUC and mean residence time (by 135% and 66%, respectively) and decreased clearance (60%), the terminal phase slope, and the volume of distribution. These findings are typical of macrolide antibiotic alteration of methylprednisolone disposition and consistent with reports of inhibition of drug metabolism by ketoconazole. Methylprednisolone reduced the 24-hour cortisol AUC by 44%, but morning cortisol concentrations returned to normal. Ketoconazole with methylprednisolone further reduced the 24-hour cortisol AUC and suppressed morning cortisol concentrations. Thus ketoconazole inhibits methylprednisolone disposition and extends the adrenal suppression effects of this corticosteroid.

Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects

“…These values are similar to literature reports for cortisol elimination. 5,22 The parameter estimates for the circadian rhythm of cortisol are of similar magnitude as reported in the literature. 22,44 For the monoexponential decay of whole blood histamine, k H , there is a difference between the 10 mg and higher doses.…”

“…8,12,13 This rapid inhibition is not affected by pretreatment with cycloheximide in a dose that inhibits protein synthesis. 14 This evidence relates well to our demonstrations in human subjects that, after intravenous administration of methylprednisolone, an initial rapid monoexponential decline of cortisol 5 and whole blood histamine occurs. These observations, together with other facts presented earlier, enable us to propose new "direct suppression pharmacodynamic models" to describe the rapid effects of glucocorticoids.…”

“…The fraction of maximum effect is as follows: (5) This is the well-known Hill equation with the Hill coefficient equal to unity. 3,24 Structurally, equation 5 is identical to the drug-receptor binding relationship: (6) in which B sP reflects specific binding, B max is maximum binding, D F is free drug concentration, and K D is the equilibrium dissociation constant of the steroid-receptor complex.…”

“…[5][6][7] These immediate effects are probably too rapid to be associated with DNA-mediated events. Recent evidence suggests that glucocorticoids inhibit proopiomelanocortin (POMC) gene transcription in the anterior pituitary lobes of rats by 10 minutes and reach maximal effects within 20 minutes.…”

Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males

“…Several compounds such as ketoconazole, metyrapone, and omeprazole (1,4,7,8) which inhibit oxidative drug metabolism have also been found to have an inhibitory effect on steroidogenesis. Ketoconazole administration has resulted in significantly decreased testosterone concentrations and side effects such as gynecomastia, decreased libido, impotence, oligospermia, and azospermia (5,16,17).…”