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Plasma Distribution, Disappearance Half-Time, Metabolic Clearance Rate, and Degradation of Synthetic Ovine Corticotropin-Releasing Factor in Man^*

WENDELL E. NICHOLSON, G. STEPHEN DECHERNEY, RICHARD V. JACKSON, C. ROWAN DEBOLD, HOWARD UDERMAN^¶, A. NANCYE ALEXANDER, JEAN RIVIER^||, WYLIE VALE^|| and DAVID N. ORTH

Department of Medicine, Vanderbilt University Medical Center Nashville, Tennessee 37232, California 92138
The Peptide Biology Laboratory, The Salk Institute San Diego, California 92138

Address all correspondence and requests for reprints to: Wendell E. Nicholson, Division of Endocrinology, A4213 Vanderbilt Medical Center North, Nashville, Tennessee 37232.

The plasma distribution, disappearance halftime, MCR, and degradation of corticotropin-releasing factor (CRF) were studied in normal men who received a pulse injection of synthetic ovine CRF (oCRF). Graded iv doses of oCRF produced a linear increase in plasma immunoreactive oCRF (IRoCRF). The calculated total plasma content of IR-oCRF 2 min after injection represented 41.7 ± 2.5% (mean ± SE) of the injected dose. The disappearance of IR-oCRF from plasma was characterized by a biexponential decay curve, with initial distribution and subsequent metabolic t values of 6.1 ± 0.5 and 55 ± 3.8 min (mean ± SE), respectively. In two subjects who were studied for 14–16 h after being given the largest dose of oCRF, there was third phase of disappearance, with a t of 198 ± 54 min. The MCR of IR-oCRF was 2.4 ± 0.2 ml/min·kg (146 ± 12 l/m²·day) and was relatively constant over a 3000-fold dose range. The volume of distribution of IR-oCRF was 6.2 ± 0.6 liters. The plasma IR-oCRF component, examined at increasing intervals after injection, was indistinguishable from the injected oCRF in that its apparent molecular size had not been altered, nor had its biological activity been attenuated. The continued circulation of apparently intact, biologically active oCRF for at least 90 min after injection was associated with sustained release of ACTH into the plasma. Thus, the clearance of oCRF from circulating human plasma is prolonged and appears to be responsible for the sustained release of ACTH that occurs after injection of this hormone-releasing factor.

^* This work was supported in part by USPHS Research Grants 5-R01-CA-11685 and 5-R25-CA-19429 from the NCI, 5-M01-RR-00095 from the General Research Center Branch of the NIH, and 5-R01-AM-26741 from the NIADDKD. Research at The Peptide Biology Laboratory was conducted in part by the Clayton Foundation for Research, California Division.

Recipient of National Research Fellowship Award 1-F32-AM-06758 from the NIADDKD.

Applied Health Sciences Fellow, National Health and Medical Research Council of Australia.

Recipient of National Research Fellowship Award 1-F32-CA-06939 from the NCI.

^¶ Recipient of a Fellowship Award from Research Training in Hypertension Grant 5-T32-HL07323.

^|| Investigator, Clayton Foundation.

Received March 22, 1983.

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