The effect of plasma protein binding on the metabolism of steroid hormones

Abstract

Earlier views indicated that globulin (corticosteroid-binding globulin (CBG) or sex hormone-binding globulin (SBG)) but not albumin binding in plasma, protects steroids from splanchnic metabolism in man. Also, the splanchnic extraction (HE) of a steroid seemed to be highly dependent on the rate of disassociation of the steroid-protein complex. However, the faster rate of disassociation (tau 1/2 = 0.9 s) of cortisol-CBG, as determined by later accurate fluorescence methods, intuitively meant that this complex must disassociate completely in a single 9 s passage through the liver. The low HE of total cortisol was then a puzzling anomaly. Using a differential equation solver (TUTSIM) and a model with unbound, albumin- and globulin-bound pools of steroid (with metabolism of unbound and also possibly albumin-bound steroid), the mechanism of splanchnic metabolism has been studied. The 'complex', probably most realistic, model includes 13 steroids, which can simultaneously bind to plasma albumin, CBG and SBG. The steroid concentration and numbers of occupied binding sites of the globulins decrease during the time of metabolism. The experimental data used are the in-vitro binding characteristics of the steroid-protein complexes, including the equilibrium constants and rates of disassociation and the in-vivo HE of nine steroids, usually measured by direct analysis of hepatic venous blood. However, the HE of cortisol had to be calculated from the metabolic clearance rate/splanchnic blood flow, giving a maximum value of 12%. The fractional metabolic rate of unbound steroid is generally represented by e. A certain value of e (RE) is required to give a remaining steroid concentration after 9 s of metabolism, which is made equal to (1-HE) in the model to simulate splanchnic extraction. If the fractional rate of metabolism of albumin-bound steroid is h (f = h/e), then RE will depend on the value of f. The maximum RE for cortisol is RE0 = 0.42 and RE1 = 0.16 for f = 0 and 1 respectively. For either value of RE, there will be the appreciable reassociation of cortisol to CBG after disassociation of the cortisol-CBG complex. With such reassociation, the total cortisol remaining after 9 s metabolism is fairly independent of the rate of dissociation of the cortisol-CBG complex. This explains the low total HE of cortisol in spite of the high rate of disassociation of cortisol-CBG.(ABSTRACT TRUNCATED AT 400 WORDS)