Roles of Plasma Clearance and Corticosteroid-Binding Globulin in the Developmental Increase in Circulating Corticosterone in Infant Rats*

The aim of this study was to determine the role of plasma clearance in the developmental increase in plasma corticosterone concentration in the infant rat. Previous studies indicated that the corticosterone rise may be mediated entirely by a decrease in the MCR. The rationale of the current study was that if this is true, then corticosterone from an exogenous source (at a constant dose) should also produce a developmental increase in circulating levels of the hormone. Therefore, infant rats, aged 12, 16, and 21 days (i.e. near the beginning, middle, and end of the endogenous corticosterone developmental rise), were adrenalectomized and provided with a constant dose of corticosterone via sc pellets. There was a significant age-related increase in plasma corticosterone in pellet-treated pups which closely paralleled that seen in sham-operated littermates. This indicates that the decrease in plasma clearance is sufficient to account entirely for the normal developmental rise in plasma corticosterone. The declining MCR for corticosterone with increasing age is due primarily to a decrease in the apparent volume of distribution (Vd), which, in turn, may result from the concurrent increase in plasma corticosteroid-binding globulin (CBG). To investigate this possibility, the Vd of dexamethasone, a synthetic glucocorticoid that does not bind to CBG, was determined and compared with that of corticosterone. While the Vd of corticosterone declined significantly with age, there was no consistent change in the Vd of dexamethasone. Taken together, these data indicate that the decrease in clearance of corticosterone from plasma with increasing age is sufficient to account for the normal developmental rise of corticosterone. Moreover, increased binding of corticosterone to CBG appears to be responsible for decreases in Vd and clearance.