Bioavailability of oral hydrocortisone in patients with congenital adrenalhyperplasia due to 21-hydroxylase deficiency

Citation
E. Charmandari et al., Bioavailability of oral hydrocortisone in patients with congenital adrenalhyperplasia due to 21-hydroxylase deficiency, J ENDOCR, 169(1), 2001, pp. 65-70
Citations number
18
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Endocrinology, Nutrition & Metabolism
Journal title
JOURNAL OF ENDOCRINOLOGY
ISSN journal
0022-0795 → ACNP
Volume
169
Issue
1
Year of publication
2001
Pages
65 - 70
Database
ISI
SICI code
0022-0795(200104)169:1<65:BOOHIP>2.0.ZU;2-H
Abstract
The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP 21) deficiency requires glucocorticoid substitution with oral hydrocortison e given twice or thrice daily. In paediatric practice little is known of th e bioavailability of oral hydrocortisone tablets used in these patients. Th e aim of this study was to assess the bioavailability of oral hydrocortison e and to evaluate current replacement therapy in the light of cortisol phar maco-kinetic properties. We determined the bioavailability of hydrocortisone following oral and intr avenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients w ere on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone ill a dose of 15 mg/m(2) body surfa ce area. Thr area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimat ed by dividing thr corrected for dose AUC after oral hydrocortisone adminis tration by che corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administrati on of hydrocortisone ill the morning, median serum total cortisol concentra tions reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2h (rang e: 0.3-3.3h) and declined monoexponentially thereafter to reach undetectabl e concentrations 7 h (range: 5-12h) after administration. Following adminis tration of the evening hydrocortisone dose, median peak cortisol concentrat ion of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range : 0.3-3.0 h) and subsequently declined gradually, reaching undetectable con centrations at 9 h (5-12 h) after administration of the oral dose. After th e intravenous hydrocortisone bolus a median peak serum total cortisol conce ntration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (r ange: 10-20 min). Serum cortisol concentrations fell rapidly and reached un detectable levels 6 h after the hydrocortisone bolus. The absolute bioavail ability of oral hydrocortisone in the morning was 94.2% (90% confidence int erval (CI): 82.8-105.5%) whereas the apparent bioavailability ill the eveni ng was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after ad ministration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous adminis tration of hydrocortisone bolus in the morning, is likely to reflect a decr ease in the hydrocortisone clearance in the evening. Decisions on the sched ule and frequency of administration in patients with congenital adrenal hyp erplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently ava ilable.