Plasma concentration‐dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone‐21‐isonicotinate

Abstract

Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03 mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 ± 2.9 days (LLOQ: 0.025 μg/L) and in urine for 9.8 ± 3.1 days (LLOQ: 0.15 μg/L). Maximum observed dexamethasone concentration in plasma was 0.61 ± 0.12 μg/L and in urine 4.2 ± 0.9 μg/L. Terminal plasma half-life was 38.7 ± 19 h. Hydrocortisone was significantly suppressed for 140 h. The plasma half-life of hydrocortisone was 2.7 ± 1.3 h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 ± 0.04 μg/L, 0.95 ± 0.04 and 6.2 ± 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.

A quantitative approach to analysing cortisol response in the horse

“…Solid lines represent data from this study (Table ), and dashed lines are data from Ekstrand et al . (). Note the variability in potencies across animals.…”

“…However, the average baseline concentration of cortisol in this study (Table , Fig. ) was lower than our previously reported values derived from morning cortisol data only but consistent with data reported in an investigation using a cosine function to describe cortisol baseline oscillation (Toutain et al ., ; Ekstrand et al ., ). The difference between our previous and present results was due to differences in study design.…”

“…The difference between our previous and present results was due to differences in study design. A morning cortisol concentration of 103.8 ± 29.1 μg/L has been reported in another studies (Soma et al ., ), which is consistent with our previously reported concentration of 93.0 ± 12.8 μg/L (Ekstrand et al ., ).…”

“…Cortisol turnover rate was characterized by circadian variation with peak plasma concentration in the morning and the lowest value occurring in the evening as previously shown in horses (Hoffsis et al ., ; Bottoms et al ., ; Toutain et al ., ; Hart et al ., ; Bohak et al ., ). Substantial within and between individual baseline variability was observed in the present study (Figs and ) and in our previous study (Ekstrand et al ., ). The variability within animals can be explained by interoccasion variability due to the episodic secretion pattern of cortisol (Toutain et al ., ).…”

Review of glucocorticoid therapy in horses. Part 1: Pharmacology

“…(Ekstrand et al . ) to horses. This activity persisted for 72 h, 96 h and 140 h for dexamethasone sodium phosphate, dexamethasone and dexamethasone 1‐21‐isonicotinate respectively.…”