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 hu man 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 mu g.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 mu g hCRF on 3 consecutive days. Noncompartmental and co mpartmental pharmacokinetic analysis was performed. Hemodynamic respon se 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.min(-1) and 345 +/- 90 mL.min (-1) for the 10-minute and 180-minute intravenous infusion, respective ly (P <.05), Corresponding elimination half-life was 45 +/- 7 minutes and 37 +/- 10 minutes. Two-compartment and 1-compartment models adequa tely described the 10-minute and 180-minute infusions, respectively. T he bioavailability of hCRF after subcutaneous administration was 67% /- 17%, Apparent clearance remained unchanged for different subcutaneo us doses. Peak plasma cortisol concentrations were similar after subcu taneous and intravenous administration of hCRF, Repetitive administrat ion of hCRF did not result in accumulation but produced a reduced plas ma cortisol response. A sigmoidal model related plasma hCRF concentrat ions to increase in heart rate (maximum, 39 beats.min-1). The relation ship between the modest decrease in diastolic blood pressure and plasm a hCRF concentrations was linear. Conclusion: The pharmacokinetics of intravenously administered hCRF were nonlinear, but apparent clearance was constant for various subcutaneous doses, An excellent bioavailabi lity and preserved bioactivity make the subcutaneous route an attracti ve choice. Repetitive administration of hCRF probably caused tolerance of the cortisol response.