Plasma protein binding of triamcinolone-H3 and hydrocortisone-4-C14.

It has become increasingly apparent in recent years that certain structural alterations of corticosteroids cause an increased biological potency of the resultant steroid (2). A number of chemical and microbiological alteration products of hydrocortisone exhibit enhanced anti-inflammatory potency coupled with unchanged or depressed mineralocorticoid activity (2, 3). As a result, steroids bearing various combinations of the Al, Gcr-CHz, 9a-F, 16a-OH, and 16cr-CHs substituents on hydrocortisone are now produced in large quantities for the treatment of various types of inflammations. We have been engaged in a series of studies on triamcinolone (9a-fluoro-ll/3,16ar,17a,21-tetrahydroxy-l,4-pregnadiene-3, 20-dione), a synthetic corticosteroid which has achieved widespread medical application. In the first paper of this series (4), we reported the effects of various substituents on the rate of disappearance of hydrocortisone derivatives from rat liver supernatant systems. The present study is concerned with the physicochemical state in which corticosteroids are transported in the plasma. The binding of steroids by plasma proteins has been reviewed by several authors (5-7). Corticosteroids in plasma are bound by a low affinity, high capacity protein fraction (albumin) and a high affinity, low capacity prot.ein fraction (designated corticosteroid-binding globulin (8, 9) or transcortin (10)). Binding of corticosteroids to each fraction depends on the number and kind of substituents present on the steroid skeleton (9,11,12). These reports prompted us to extend our investigation of the biochemical effects of multiple structural alterations of hydrocortisone to an examination of plasma protein binding of the synthetic steroids. Both the whole plasma and the albumin binding of triamcinolone were determined and compared with similar experiments on hydrocortisone. In addition, the effect of various substituents on transcortin-steroid binding was investigated in a series of experiments on the effects of hydrocortisone derivatives on the plasma binding of hydrocortisone. Unlike hydrocortisone (8, 9), triamcinolone was not bound extensively to transcortin in human or dog plasma. In addition, triamcinolone was bound to a lesser extent than hydrocortisone by solutions of plasma albumin. Thus, at any given concentration, a greater percentage of triamcinolone than of hydrocortisone would be present in the unbound state. The relationship