Abstract
New drugs that enhance metabolism or clearance of thyroid hormones in rats often trigger a sequence of toxicity events during chronic administration: reduction of thyroxine, elevation of thyroid-stimulating hormone (TSH) levels, and thyroid gland hyperfunction/growth. Hepatocellular hypertrophy and thyroid follicular hyperplasia are often observed with increased liver and thyroid organ weights. This unique toxicity profile seems to be species-specific because the thyroxine in rodents is metabolized rapidly, without thyroid hormone-binding globulin that serves as a reserve, as in humans. Thus, elevations of TSH were not reported in humans for drugs such as delavirdine, fluvastatin, nicardipine, phenobarbital, simvastatin, and spironolactone, all of which produce thyroid hyperplasia or tumors in rats. Further, the human thyroid is less sensitive to prolonged TSH stimulation than that of the rat (eg, endemic goiter patients with high TSH due to iodine deficiency do not develop thyroid cancer). In view of the species difference in sensitivity of the thyroid between rodents and humans, using the rat as an animal model to explore target organs of toxicity for a new drug that significantly enhances thyroid hormone metabolism/clearance...Continue Reading
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