Orphenadrine citrate (Norflex) mediated inhibition of thyroid function in the adult male rat.

Abstract

The hydrochloride salt of orphenadrine (Disipal® ) in man is known to cause an increase in total serum thyroxine (T4) as measured by competitive binding technique (CPB) but not by RIA. The latter implies a direct in vitro competition between T4 and orphenadrine metabolites for T4 binding sites on TBG. The present study was designed to evaluate whether orphenadrine citrate (Norflex® ) has a direct effect on the thyroid gland in male rats. In contrast with the studies reported in humans, the chronic administration (32 days) of orphenadrine citrate to rats led to a gradual depression of serum thyroxine (T4), free thyroxine (FT4), and triiodothyronine (T3) without affecting the serum rat thyrotropin (rTSH) levels in these animals. Orphenadrine citrate administration was accompanied by important ultrastructural changes in the thyroid gland characterized by the absence of colloid droplet formation 15 min following TRH-induced TSH release and the preservation of numerous exocytotic vesicles. These ultrastructural findings are consistent with the blocking effect of orphenadrine citrate on the endocytotic and possibly exocytotic process. The above findings could not be attributed to a difference in rTSH response of control groups and orphenadrine citrate treated rats following TRH administration. The fact that the orphenadrine citrate treated rats, despite their very low FT4 levels, did not develop an elevated serum TSH level suggested that a central mechanism was involved as well. Although the serum rTSH and rat prolactin (rPRL) responses following TRH administration were similar in both control and experimental groups, the mean serum rPRL level was significantly lower in the orphenadrine citrate-treated group when compared with the saline control group on day 26 of the study [orphenadrine citrate = 36.0 ±4.3 ng/ml (SE), n = 9, vs control = 51.9 ±4.7, n = 11 (p >0.01)]. No significant differences in the pituitary rTSH content of orphenadrine citrate-treated rats and control rats were observed. In contrast, the pituitary rPRL was significantly depressed in the orphenadrine citrate treated rats when compared with the control group [orphenadrine citrate = 5.9 ± 0.63 /ig/ml pituitary protein, n=8,vs saline control = 11.43 ± 1.58 /ig/ml pituitary protein, n = 10 (p>0.01)]. The fall in the biochemical parameters of thyroid function in orphenadrine citrate treated rats in conjunction with the ultrastructural findings suggests a direct effect of orphenadrine citrate or one of its metabolites on the thyroid itself. Additional studies suggest a central effect of orphenadrine citrate as well. The exact mechanism by which orphenadrine citrate produces these findings remains to be elucidated.