Rats treated with
temelastine (SK&F 93,944), a novel
histamine H1-receptor antagonist, develop thyroid lesions characterized by
hypertrophy and
colloid depletion. To investigate the mechanism underlying the lesion the biliary clearance and hepatocellular accumulation of radio-labelled iodothyronines was measured in rats or cultured rat hepatocytes. Treatment with
temelastine increased both the biliary clearance (approximately 300% of control) and hepatocellular accumulation (approximately 200%) of
thyroxine (T4) but had little or no effect on tri-iodothyronine (T3). Chromatographic analysis of bile samples from
temelastine-treated rats showed that the majority (approximately 78%) of T4 was present in the unconjugated form. This contrasted with data from
phenobarbitone-treated rats which showed that approximately 80% of T4 in the bile was present as the
glucuronide conjugate. Studies with cultured hepatocytes showed that the hepatocellular accumulation of T4 was energy dependent. At 4 degrees C the treatment-related increases in accumulation of T4 were abolished, suggesting that
temelastine is specifically affecting the high affinity, energy dependent system which preferentially transports
thyroxine into hepatocytes. Because
temelastine is metabolized extensively, investigations were undertaken to discover if the hepatic effects were caused by the parent compound or an oxidative metabolite. The results showed that the hepatocellular accumulation of T4 remained increased in hepatocytes co-incubated with
temelastine and
1-aminobenzotriazole (a suicide inhibitor of
cytochrome P450), even though no measurable P450 could be found in the cells. Also, in studies with two major "rat" metabolites of
temelastine, i.e. 93,944-Met I or 93,944-Met VIII, treatments failed to reproduce the responses seen with the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)