Pharmacokinetics of dexamethasone with pharmacokinetic/pharmacodynamic model of the effect of dexamethasone on endogenous hydrocortisone and cortisone in the horse

Abstract

A compartmental model was used to describe the pharmacokinetics of dexamethasone (DXM) and changes in the plasma concentration of endogenous cortisone (COR) and hydrocortisone (HYD) following intravenous (i.v.) administration of DXM (0.05 mg/kg) in horses. Quantification of DXM, COR and HYD in equine plasma was achieved using liquid chromatography interfaced with triple spray quadrupole quantum tandem mass spectrometry (LC/TSQ-MS/MS). The median alpha (t(1/2alpha)), beta (t(1/2beta)), and gamma (t(1/2gamma)) half-lives were 0.33, 2.2, and 10.7 h respectively. The area under the DXM plasma concentration curve (AUC) was 113.5 ng.h/mL. At 72 h post-DXM administration, the plasma concentration of DXM in all horses was below the level of quantification (100 pg/mL). The baseline plasma concentration of COR was 3.5 +/- 0.69 ng/mL and declined significantly (P < 0.02) to 2.9 +/- 0.86 ng/mL at 1 h. The nadir in COR plasma concentration was 0.65 +/- 0.12 ng/mL at 28.8 +/- 9.0 h, and the DXM plasma concentration was 0.19 +/- 0.13 ng/mL. COR concentration returned to baseline at 96 h. Baseline plasma concentration of HYD was 58.8 +/- 11.7 ng/mL and declined significantly (P < 0.001) to 41.1 +/- 14.9 ng/mL at 1 h following DXM administration but recovered to baseline at 96 h. The sensitivity of LC/TSQ-MS/MS allowed complete description of the pharmacokinetics of DXM and its effect on plasma concentrations of both COR and HYD.

Pharmacokinetics of methylprednisolone acetate after intra-articular administration and its effect on endogenous hydrocortisone and cortisone secretion in horses

“…In the present study, the cessation of production and the subsequent decrease in plasma concentrations of HYD and COR after IA administration of MPA occurred at a later time and a higher drug concentration than that reported after IV administration of dexamethasone. 33 This may be related to the slower increase in the plasma concentration of MP and its lower potency, compared with dexamethasone.…”

“…The t ½ values for COR and HYD in our study (approx 1.0 and 1.2 hours, respectively) were similar to those previously reported in humans and horses. [31][32][33][34] The initial step in the development of a biological response to the administration of corticosteroids is the rapid diffusion from plasma into cells for interaction with cytosolic receptors. 35 Most of these endogenous and synthetic corticosteroids are lipid soluble; they enter the target cell organs and bind with intracellular receptors.…”

Daily endogenous cortisol production and hydrocortisone pharmacokinetics in adult horses and neonatal foals

“…Dexamethasone suppression protocol development in foals-Because the efficacy of the dexamethasone suppression protocol is known in adult horses 38,39 but has not been evaluated in foals, a preliminary trial in foals was conducted. Six Quarter Horse foals (3 males and 3 females) other than those used for serum cortisol measurements were used to determine an appropriate dexamethasone suppression protocol for use in the study.…”

Anti-inflammatory Drugs in Equine Neonatal Medicine. Part II: Corticosteroids

“…Suppression of cortisol secretion, which indicates adrenal gland suppression, developed subsequent to administration of glucocorticoids via IV, intramuscular (IM), or with inhalant methods. Short-term parenteral administration of dexamethasone, prednisolone sodium succinate, aerosolized beclomethasone dipropionate, and hydrocortisone was not associated with adrenocortical insufficiency as evaluated by response to ACTH stimulation testing [13,[16][17][18][19]22]. Dexamethasone was administered at 0.05 mg/kg in a single injections, IV and IM [16,17], at 0.044 and 0.088 mg/kg at 5-day intervals for a total of six injections [13], at 0.044 mg/kg with a single IM injection [18] and at 0.1 mg/kg once a day [19].…”

“…In adult horses, exogenous systemic glucocorticoid administration has been associated with adverse effects such as hypothalamic-pituitary-adrenal (HPA) axis suppression, muscle wasting, hyperglycemia, polyuria, polydipsia, immunosuppression, and laminitis [11][12][13][14][15][16][17][18][19][20][21]. Some studies were performed to investigate adrenocortical function in response to exogenous glucocorticoids in horses [12][13][14][15][16][17][18][19][20][21][22]. Suppression of cortisol secretion, which indicates adrenal gland suppression, developed subsequent to administration of glucocorticoids via IV, intramuscular (IM), or with inhalant methods.…”