title: 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.
authors.affiliation: Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Ekstrand
authors.forename: U
authors.initials: U
authors.lastname: Bondesson
authors.forename: J
authors.initials: J
authors.lastname: Gabrielsson
authors.forename: M
authors.initials: M
authors.lastname: Hedeland
authors.forename: P
authors.initials: P
authors.lastname: Kallings
authors.forename: L
authors.initials: L
authors.lastname: Olsén
authors.forename: C
authors.initials: C
authors.lastname: Ingvast-Larsson
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D006736:Horses / Q000378:metabolism* / Q000502:physiology; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000097:blood*; D007273:Injections, Intramuscular / Q000662:veterinary; D008297:Male
chemical_list: D001549:Benzamides; C105049:nibentan; D006854:Hydrocortisone