Comparison of the hypothalamic-pituitary-adrenal axis susceptibility upon single-dose i.m. depot versus long-acting i.v. triamcinolone acetonide therapy: a direct pharmacokinetic correlation.
The effects of single injections of glucocorticoid (GC) depot suspension and of long-acting GC were studied in conscious dogs. Both the depot suspension GC triamcinolone-16,17-alpha-acetonide (TAA) and the long-acting triamcinolone acetonide-21-dihydrogen phosphate (TAA-DHP) decreased basal and ACTH-stimulated cortisol levels and in a specific time-dependent way. Before treatment, all dogs had normal basal and peak cortisol responses to ACTH challenge (13-15 and > 120 nmol/l at 1 h respectively). Intravenous TAA-DHP reduced cortisol levels for 12 h, i.m. TAA reduced cortisol levels as of 1.5 h and the effect lasted for at least 4 weeks. Both treatments blunted the peak response to ACTH. ACTH elevated cortisol levels to or above baseline values within 10 days following TAA-DHP treatment, but the TAA treatment suppressed an ACTH response for at least 4 weeks. Kinetic analysis of both the preparations demonstrated rapid absorption (tmax, 0.6-1.5 h) and low maximum plasma concentrations (peak Cmax, 2.99-5.51 nmol/l) of the steroids; indeed, the terminal half-life of TAA-DHP (13.9 +/- 1.3 h) was very much shorter than that of TAA (125.9 +/- 15.8 h). In addition, the mean residence time differed very much (11 vs 160 h for TAA-DHP and TAA respectively), in line with a delayed elimination of the depot compared with the long-acting formulation. Application of these TAA formulations needs careful evaluation for their surprisingly different effects on endocrine stress axis activity.
Abraham
Getu
G
Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, An den Tierkliniken 15, D-04103 Leipzig, Germany. gabraham@rz.uni-leipzig.de
Demiraj
Fioralba
F
Ungemach
Fritz Rupert
FR
D000324:Adrenocorticotropic Hormone; D000818:Animals; D003692:Delayed-Action Preparations; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011897:Random Allocation; D014222:Triamcinolone Acetonide / Q000008:administration & dosage* / Q000493:pharmacokinetics
D003692:Delayed-Action Preparations; D000324:Adrenocorticotropic Hormone; D014222:Triamcinolone Acetonide; D006854:Hydrocortisone