Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men.

D-Ala2-GHRH-(1-29) has increased binding affinity and exhibits enhanced biological activity in man. It is not known whether changes in the metabolic clearance of this and other GHRH analogs contribute to their increased biological activity. GHRH-(1-29)-NH2 and D-Ala2-GHRH-(1-29)-NH2 were administered by constant iv infusion at a rate of 25 ng/kg.min to 10 normal men. Blood was sampled during the 90-min infusion and for 20 min afterward and assayed for the infused analog. The MCR of the D-Ala2 analog (mean +/- SE) was significantly less (21 +/- 1.2 mL/kg.min) than that of GHRH-(1-29)-NH2 (39.7 +/- 3.9 mL/kg.min; P < 0.001). The disappearance half-time of the D-Ala2 analog was 6.7 +/- 0.5, whereas that of GHRH-(1-29)-NH2 was 4.3 +/- 1.4 min (P < 0.05). These findings demonstrate that the D-Ala2 substitution contributes to the enhancement of biological activity by reducing metabolic clearance.