Corticotropin releasing factor (CRF) has recently been identified, purified and shown to be a 41-amino acid polypeptide that stimulates secretion of beta-endorphin and ACTH. The metabolic clearance rates (MCR) of I125-CRF and I125-TyroCRF were measured in cynomologus monkeys using the pulse injection and the continuous infusion methods. Hunter-Bolton reagent was used for iodination of CRF and the chloramine-T method for Tyro-CRF. Gel chromatography was used to separate free iodine (and radioiodinated small fragments) from iodinated CRF in plasma samples. Disappearance of I125-CRF or I125-Tyro-CRF could be modeled with two components (bi-exponential). Plasma half-life of I125-CRF was 17.1 +/- 2.44 min (mean +/- SE, n=4) for the fast component and 198 +/- 5.3 min for the slow component. The MCR of I125-CRF using the pulse injection technique was 0.44 +/- 0.06 L/Kg/d, n=4 and the volume of distribution 213.5 +/- 12 ml, n=4, roughly equal to the plasma volume. Continuous infusion of I125-CRF and of I125-Tyro-CRF gave MCR's ranging between 2.23 -= 5.08 L/Kg/d, n=4. I125-ACTH MCR, measured for comparison using the same technique, was 5-10 fold higher. Thus, the plasma half-life of CRF is longer than for all other known hypothalamic peptides and its metabolic clearance rate relatively low and considerably less all other known hypothalamic peptides and its metabolic clearance rate relatively low and considerably less than that of ACTH. Strong binding of CRF to plasma proteins may be responsible for the small volume of distribution and lower MCR values for the pulse injection method.