Effects of a New Hypolipidemic Agent, MK-185, on Serum Thyroxine-Binding Globulin (TBG) and Dialyzable Fraction Thyroxine

MK-185 (halofenate) is a hypo-lipidemic agent which has been shown in short-term clinical trials in hyperlipidemic patients to decrease serum total thyroxine (T4) and to increase serum dialyzable fraction T4 (DFT4). In polyacrylamide gel electrophoresis studies reported here, MK-185 is shown to compete with T4 for binding sites on serum thyroxine-binding globulin (TBG); MK-185 (2.9 × 10−3M concentration n i serum) reduced TBG binding of tracer level T4 by 47%. The agent also has a small effect on albumin-binding of T4. The effects of MK-185 on T4 distribution in serum were seen in electro-phoretic studies both at pH 9.0 and pH 7.4. T-3 binding by TBG was also noted to be inhibited by MK-185. Radioactive MK-185 is bound discretely to albumin, but diffuse binding was also noted through the α- and β-globulin regions on electrophoresis. In equilibrium dialysis studies the in vitro addition of MK-185 (100 μg/ml) to serum led to 140% increase in DFT4, and as little as 2μg MK 185/ml produced a detectable increase in DFT4. The latter level of MK-185 in serum approximates clinically achievable serum concentrations of the drug. The administration of MK-185 to hyperlipidemic patients results in effects on T4 in serum which can be attributed to the T4-displacing effect of the agent shown in the present data. However, certain inconsistencies in the reported clinical observations on serum absolute free T4, together with the recently recognized action of another in vitro inhibitor of TBG (diphenylhydantoin) on peripheral clearance of T4, suggest that displacement effect, alone, may be inadequate to explain MK-185 effects on serum T4.