Pharmacokinetics, cortisol release, and hemodynamics after intravenous and subcutaneous injection of human corticotropin-releasing factor in humans.
OBJECTIVE
Two clinical trials investigated the pharmacokinetics of human corticotropin-releasing factor (hCRF), resulting cortisol release, and associated hemodynamic changes.


METHODS
In a 3 x 3 Latin square design, subjects were randomized to receive a single dose of 5 microg x kg(-1) hCRF as a 10-minute intravenous infusion, a 180-minute infusion, and a subcutaneous injection in separate study sessions 7 days apart. Twelve additional subjects obtained a subcutaneous dose of either 300, 600, or 1200 microg hCRF on 3 consecutive days. Noncompartmental and compartmental pharmacokinetic analysis was performed. Hemodynamic response was characterized with use of pharmacodynamic models.


RESULTS
The volume of distribution at steady state was 9.81 +/- 3.0 and 15.61 +/- 2.9, and the clearance was 256 +/- 40 mL x min(-1) and 345 +/- 90 mL x min(-1) for the 10-minute and 180-minute intravenous infusion, respectively (P < .05). Corresponding elimination half-life was 45 +/- 7 minutes and 37 +/- 10 minutes. Two-compartment and 1-compartment models adequately described the 10-minute and 180-minute infusions, respectively. The bioavailability of hCRF after subcutaneous administration was 67% +/- 17%. Apparent clearance remained unchanged for different subcutaneous doses. Peak plasma cortisol concentrations were similar after subcutaneous and intravenous administration of hCRF. Repetitive administration of hCRF did not result in accumulation but produced a reduced plasma cortisol response. A sigmoidal model related plasma hCRF concentrations to increase in heart rate (maximum, 39 beats x min(-1)). The relationship between the modest decrease in diastolic blood pressure and plasma hCRF concentrations was linear.


CONCLUSIONS
The pharmacokinetics of intravenously administered hCRF were nonlinear, but apparent clearance was constant for various subcutaneous doses. An excellent bioavailability and preserved bioactivity make the subcutaneous route an attractive choice. Repetitive administration of hCRF probably caused tolerance of the cortisol response.
Angst
M S
MS
Department of Anesthesia, Stanford University School of Medicine, Calif 94305-5117, USA.
Dyck
J B
JB
Azarnoff
D L
DL
Goldblum
R
R
Ho
B
B
Gfroerer
T
T
Linton
E A
EA
Glynn
B P
BP
Shafer
S L
SL
D000328:Adult; D000704:Analysis of Variance; D001682:Biological Availability; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male
D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone