Preclinical development of new drugs that enhance thyroid hormone metabolism and clearance: inadequacy of using rats as an animal model for predicting human risks in an IND and NDA

American Journal of Therapeutics
Kuei-Meng Wu, James G Farrelly

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

References

Jul 26, 1991·Biochimica Et Biophysica Acta·L SavuI L Flink
Apr 1, 1989·Toxicology and Applied Pharmacology·D E SemlerF M Radzialowski
Feb 9, 1993·Biochemical Pharmacology·J A van RaaijK J van den Berg
Jul 1, 1995·European Journal of Drug Metabolism and Pharmacokinetics·M OhtawaH Tojo
Jan 1, 1996·Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology·R J GriffinM L Cunningham
Dec 1, 1996·Toxicology and Applied Pharmacology·R C BookstaffA Parkinson
Apr 1, 1997·Regulatory Toxicology and Pharmacology : RTP·J F ContreraJ J DeGeorge
Jul 29, 1998·Environmental Health Perspectives·R N HillD V Singh
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·R H Tukey, C P Strassburg
Jan 28, 2004·Birth Defects Research. Part B, Developmental and Reproductive Toxicology·Neepa Y ChoksiMichael Shelby

❮ Previous
Next ❯

Citations

Mar 8, 2008·Expert Opinion on Drug Safety·Mark R Fielden, Kyle L Kolaja
Dec 21, 2014·Regulatory Toxicology and Pharmacology : RTP·Joanne A LasradoKelli A Herrlinger
Aug 15, 2014·Toxicologic Pathology·Prashant R NambiarGregory L Finch
Aug 24, 2013·Toxicologic Pathology·Daniel MortonNancy Bower
Nov 2, 2018·Annals of the New York Academy of Sciences·Francesca PistollatoMaurizio Battino
Mar 31, 2012·Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews·Jeffrey FisherDavid Mattie
Mar 13, 2014·Menopause : the Journal of the North American Menopause Society·Marnie G SilversteinCarol A Shively
Sep 3, 2020·EFSA Journal·UNKNOWN EFSA Panel on Contaminants in the Food Chain (CONTAM)Elsa Nielsen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.