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Interactions between Oleic Acid and Drug Competitors Influence Specific Binding of Thyroxine in Serum^*

Ewen Downie Metabolic Unit, and Monash University Department of Medicine, Alfred Hospital Melbourne, Victoria 3181, Australia

Address all correspondence and requests for reprints to: J. R. Stockigt, M.D., Ewen Downie Metabolic Unit, Alfred Hospital, Commercial Road, Melbourne, Victoria 3181, Australia.

Long chain nonesterified fatty acids and various drugs may share albumin-binding sites in common. We questioned whether serum binding of T₄ could be indirectly influenced by displacement of drug competitors from these sites by nonesterified fatty acids. The influence of oleic acid on druginduced inhibition of [¹²⁵I]T₄ binding was measured by equilibrium dialysis, using undiluted serum in order to avoid dilutionrelated artefacts. Oleic acid (1 mmol/L) alone did not inhibit serum protein binding of T₄, but this concentration augmented the inhibitory effects on T₄ binding of diflunisal, mefenamic acid, meclofenamic acid, and aspirin. This effect increased with increasing concentrations of mefenamic acid, meclofenamic acid, and furosemide. The T₄-displacing effect of fenclofenac was not augmented by oleic acid. The mechanism of these interactions was studied by examining 1) oleic acid effects on drug binding, and 2) drug effects on oleic acid binding in undiluted serum.

Increments in added oleic acid (0.5–2.0 mmol/L) progressively increased the mean unbound fractions of [¹⁴C]aspirin, [¹⁴C] diflunisal, and [¹⁴C]furosemide, but did not displace [¹⁴C]fenclofenac. At the relevant total and free drug concentrations, the inhibitory effect of oleic acid on drug binding and its influence on drug-induced displacement of T₄ were concordant in the order: meclofenamic acid > aspirin > mefenamic acid > diflunisal > furosemide > fenclofenac. In contrast, drug-induced increases in the unbound fraction of [¹⁴C]oleic acid did not correlate with augmentation of T₄ displacement. We conclude that synergistic effects of oleic acid and drugs on T₄ binding result from drug displacement by oleic acid, rather than the reverse effect. Hence, substances that increase the unbound concentration of a competitor by displacing it from albumin can increase its T₄-displacing potency. Interactions between various ligands may exert a greater hormone-displacing effect than the sum of each alone.

^* Presented in part at the 33rd Annual Scientific Meeting of the Endocrine Society of Australia, Perth, September 1990, and at the 10th International Thyroid Congress, The Hague, The Netherlands, February 1991. This work was supported in part by Project Grants 850366 and 880859 from the National Health and Medical Research Council of Australia and an equipment grant from the Alfred Hospital Whole-Time Medical Specialists' Private Practice Scheme.

Received February 11, 1991.

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