Partial pharmacodynamic model for the circadian-episodic secretion of cortisol in man

A pharmacodynamic model was developed to facilitate computer analysis of the circadian-episodic influx of cortisol into plasma from the adrenal gland. The model consists of a catenary system of a biorhythmic control, the adrenal gland, and a body compartment containing circulating cortisol. Computer nonlinear regression analysis was carried out on data consisting of plasma cortisol concentrations measured at 30-min intervals over 1 day in a group of normal children. Circadian rhythmic synthesis of cortisol by the adrenal gland was described by a sinusoidal function which provides the level (284 plus or minus 50 mugg/h/m2) and amplitude (245 plus or minus 50 mug/h/m2) of the synthesis rate and the period (24 hours) and acrophase (8.14 plus or minus 1.95 h) of the cycle. Cosinor analysis of the data confirmed a highly significant circadian rhythm in the daily synthesis rate of cortisol. Episodic secretion, described by an empirical switch function, is assumed to result from accumulation of small amounts of cortisol precursors in the adrenal gland and intermittent stimulation of cortisol release by ACTH. This was found to take place over 46.6 plus or minus 2.4% of a 24-h day. Circulating cortisol is contained in a single body compartment with an apparent volume of distribution (5.3 plus or minus 0.55 liters/m2) from which elimination occurs by first-order metabolic clearance. The biological half-life averaged 0.96 plus or minus 0.18 h. Upon least-square optimization of selected kinetic parameters, the circadian-episodic model increases the accountable variation (r2 x 100) to 89% in comparison with the 35% obtained by use of only a periodic function.