Effect of the multidrug resistance modulator valspodar on serum cortisol levels in rabbits.
OBJECTIVE
To contribute to a better understanding of the physiological role of P-glycoprotein (P-gp) in the adrenal gland, we initiated our studies in rabbits. The aim of our study was to explore the effect of the selective multidrug resistance (MDR) modulator PSC 833 (valspodar) on serum cortisol in rabbits.


METHODS
Baseline and corticotropin-stimulated serum cortisol levels were measured before and after valspodar treatment in adult male rabbits. Seven rabbits were treated with 50 mg/kg per dose and seven, with 75 mg/kg per dose of valspodar subcutaneously. Serum cortisol levels were determined by radioimmunoassay adjusted for expected values.


RESULTS
Serum cortisol levels (baseline as well as corticotropin-stimulated) increased after both valspodar treatment regimens. The increase was dose-dependent and was higher for the baseline than for the corticotropin-stimulated values. Serum valspodar levels exceeding 1000 ng/ml were achieved in all except one animal in each group. We hypothesize that the increased serum cortisol levels were due to increased adrenocorticotropic hormone (ACTH) secretion after valspodar treatment, but, unfortunately, we could not measure ACTH properly in rabbits by means of the commercially available kits.


CONCLUSIONS
Our study indicates that P-gp is not involved in steroid hormone secretion in the adrenal gland. This is evident from observations that serum cortisol levels were found to have increased rather than decreased in rabbits treated with a P-gp blocker and that the treated animals appeared healthy and normal. Since P-gp was found to play an important role in protection against xenobiotics in some other organs, further studies to explore the protective role of P-gp in the adrenal gland are warranted.
Cufer
T
T
Institute of Oncology, Ljubljana, Slovenia.
Vrhovec
I
I
Pfeifer
M
M
Skrk
J
J
Borstnar
S
S
Sikic
B I
BI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D003524:Cyclosporins / Q000097:blood / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006854:Hydrocortisone / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011817:Rabbits
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D000324:Adrenocorticotropic Hormone; C070272:valspodar; D006854:Hydrocortisone