title: Hypercortisolemia decreases dexamethasone half-life in rabbit.
abstract: The pharmacokinetics of dexamethasone have been found to be related to endogenous hypothalamic-pituitary-adrenal (HPA) axis activity. Lower plasma dexamethasone levels in psychiatric patients (especially depressed) who are dexamethasone suppression test (DST) nonsuppressors have previously been reported. Since DST nonsuppression is one measure of HPA axis hyperactivity and is usually associated with relatively increased plasma cortisol levels and lower post dose plasma dexamethasone levels, we hypothesized that hypercortisolemia can induce a more rapid disappearance of dexamethasone from plasma. We therefore studied the kinetics of dexamethasone in rabbits before and after a period of sustained hypercortisolemia produced by administration of IM hydrocortisone acetate, a slowly absorbed salt of cortisol. Mean dexamethasone half-life decreased significantly from baseline of 1.92 h on day zero in seven rabbits to 1.17 h on experimental day 17 of induced hypercortisolemia (P < 0.001), while there was no significant change in saline treated controls (n = 3). Dexamethasone half-life had returned to the baseline levels when retested 88 days later on experimental day 105. The results indicate that pronounced hypercortisolemia decreases dexamethasone half-life in rabbits, and support the concept that increased circulating cortisol levels induce hepatic enzymes that metabolize dexamethasone. Thus, the lower postdexamethasone plasma dexamethasone levels and decreased dexamethasone half-life in DST nonsuppressors may in part reflect the effect of prior or coincident hypercortisolemia.
authors.affiliation: Department of Psychiatry, Cornell Medical College, New York, NY, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Stokes
authors.forename: P M
authors.initials: PM
authors.lastname: Stoll
authors.forename: J H
authors.initials: JH
authors.lastname: Schluger
authors.forename: B
authors.initials: B
authors.lastname: Lasley
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood*; D003907:Dexamethasone / Q000097:blood*; D006854:Hydrocortisone / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D011817:Rabbits; D011897:Random Allocation
chemical_list: D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D006854:Hydrocortisone