CYCLOSPORINE-A INCREASES SERUM CORTISOL-LEVELS IN RABBITS

P-glycoprotein (P-gp), a membrane protein that was originally found to be involved in the efflux of cytotoxic drugs out of the tumor cells, is also present in a variety of normal human and animal tissues, such as the adrenal cortex. The function of P-gp in the adrenal cortex has not been defined yet, The aim of our study was to determine whether th e blockade of P-gp by cyclosporine A (CsA) dissolved in Cremophor EL ( Crem) inhibits cortisol secretion in rabbits. In 14 rabbits, the basel ine and ACTH stimulated serum cortisol levels were measured before and after CsA treatment. Seven rabbits were treated with 2 x 30 mg/kg CsA and seven with 2 x 90 mg/kg CsA injected s,c. Serum cortisol levels w ere determined by radioimmunoassay adjusted for expected values, The w hole blood CsA levels were determined by a commercially available fluo rescence polarization immunoassay. Serum cortisol levels, both baselin e and ACTH stimulated, significantly increased after both low and high dose CsA treatment. The increase was dose dependent. The mean baselin e cortisol levels increased from 5.7 (So = 6.3) to 15.0 nmol/l (Sc = 7 .2) in the low dose group and from 7.7 (SD = 4,9) to 44.9 nmol/l (SD = 13.8) in the high dose group, The mean cortisol levels 8 h after ACTH stimulation increased from 53.3 (Sc = 34.5) to 106.0 nmol/l (SD = 33, 0) in the low dose group and from 47.7 (SD = 12,2) to 153.0 nmol/l (SD = 55,1) in the high dose group. The mean whole blood CsA levels measu red at that time were 1782 mu g/l (SD = 634) in the low dose group and 2428 mu g/l (Sc = 483) in the high dose group, Contrary to our expect ations, CsA treatment increased serum cortisol levels, both baseline a nd ACTH stimulated, in rabbits. The increase may or may not be related to the drug's interaction with P-gp, Further studies to explore our s urprising finding and adrenal as well as pituitary gland function unde r P-gp inhibitors are warranted.