Treatment with flutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasia.
BACKGROUND
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by a defect in cortisol and often aldosterone secretion, and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenocortical androgen secretion. Anti-androgen therapy with flutamide is an option that allows control of hyperandrogenism without recourse to supraphysiological doses of glucocorticoid.


METHODS
We examined the pharmacokinetic parameters of hydrocortisone administered i.v. as a bolus at a dose of 15 mg/m2 in a 17.3 year-old female patient with classic CAH before and four weeks after institution of flutamide treatment by determining serum cortisol concentrations at 10 min intervals for 6 h following the i.v. bolus of hydrocortisone.


RESULTS
Treatment with flutamide resulted in a decrease in cortisol clearance from 420 ml/l to 305 ml/l (27% reduction), and a decrease in volume of distribution from 51.61 to 451 (12.9% reduction). The half-life of cortisol increased from 85.3 min to 102.1 min.


CONCLUSIONS
Flutamide treatment decreases cortisol clearance, thereby prolonging its half-life. These findings indicate that a reduction in the daily dose of glucocorticoid replacement may need to be considered when flutamide is added to the treatment regimen of patients receiving hydrocortisone.
Charmandari
E
E
London Centre for Paediatric Endocrinology, University College London, UK. charmane@mail.nih.gov
Johnston
A
A
Honour
J W
JW
Brook
C G D
CG
Hindmarsh
P C
PC
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D019540:Area Under Curve; D005260:Female; D005485:Flutamide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000097:blood* / Q000627:therapeutic use; D017588:Hyperandrogenism / Q000188:drug therapy / Q000209:etiology; D013256:Steroids / Q000627:therapeutic use
D000726:Androgen Antagonists; D000893:Anti-Inflammatory Agents; D013256:Steroids; D005485:Flutamide; D006854:Hydrocortisone