Mechanistic investigation of species-specific thyroid lesions induced by treatment with the histamine H1 antagonist temelastine (SK&F 93944) in rats.
Temelastine (SK&F 93944), an H1 histamine receptor antagonist, induces thyroid histopathological lesions in the rat, indicative of thyroid follicular cell stimulation, at oral doses of 10-33 mg/kg body weight/day. These changes do not occur in the dog or mouse. Endocrinological short-term studies support an increased thyroid follicular activity (increased radioiodide accumulation) with decreased circulating thyroxine (T4) at oral doses at or above 300 mg/kg body weight/day and increased circulating thyroid stimulating hormone (TSH). This is thought to be responsible for the thyroid follicular stimulation following Temelastine treatment. No direct inhibition of thyroid function occurs. Temelastine produces these species-specific changes by enhancing thyroxine clearance from the circulation in the rat, but not in the dog or mouse. In vitro studies with cultured rat hepatocytes suggest that the mechanism behind these changes is a drug-induced increase of hepatocellular T4 binding and uptake which leads to an enhanced metabolic clearance of the hormone.
Atterwill
C K
CK
Smith Kline & French Research Ltd, The Frythe, Welwyn, Herts., England.
Poole
A
A
Jones
C
C
Jones
R
R
Brown
C
C
D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D007457:Iodine Radioisotopes; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008713:Methimazole / Q000494:pharmacology; D051379:Mice; D011744:Pyrimidinones / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012974:Sodium Iodide / Q000378:metabolism; D013045:Species Specificity; D013194:Staining and Labeling; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D013963:Thyroid Hormones / Q000097:blood*; D013972:Thyrotropin / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism / Q000493:pharmacokinetics
D006634:Histamine H1 Antagonists; D007457:Iodine Radioisotopes; D011744:Pyrimidinones; D013963:Thyroid Hormones; D008713:Methimazole; D013972:Thyrotropin; C049054:temelastine; D012974:Sodium Iodide; D013974:Thyroxine