Effects of an inhibitor of hepatic drug metabolism, 2-diethylaminoethyl-2,2-diphenylvalerate HCl (SKF 525-A), on thyroxine metabolism in the rat.

Abstract

We have examined some effects of 2ndash;diethylaminoethyl- 2,2-diphenylvalerate HC1 (SKF 525-A), an inhibitor of hepatic drug metabolism and of cytochrome P-450-mediated reactions, on T4 metabolism by rat liver slices and by rats in vivo. Incubation of liver slices with labeled T4 in medium containing 0.1 mM SKF 525-A reduced deiodination to 27% of control and did not affect T3 formation; at 1.0 mM SKF 525-A, deiodination and T3 formation both declined (to 7% and 60% of control levels, respectively), while degradation of rT3 was not affected. Hypoxia had effects similar to SKF 525-A, i.e. inhibition of T4 deiodination, while formation of T3 from T4 and degradation of rT3 were not inhibited. During a constant infusion of [125I]T4, SKF 525-A (3.5 mg/100 g BW, ip) caused an acute increase in the MCR of T4. It was then found that SKF 525-A added to serum in vitro increased the free T4 fraction; injected in vivo, it caused a prompt rise in the free T4 fraction accompanied by a fall in serum TSH. In rats receiv...