Aims NTBC (2-(2-nitro-4-¯uoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. Methods A total of 28 volunteers participated in two separate studies with the compounds. In the ®rst study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Results Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg kg x1 body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (t s.d.) AUC(0,?) (capsule 602t154 vs solution 602t146 mg ml x1 h) or t 1/2 (capsule 55t13 vs solution 54t8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a signi®cant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,?) and C max increased linearly with dose. Following administration of 1 mg NTBC kg x1 in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol ml x1 . Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol ml x1 following a dose of 4 mg kg x1 body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione kg x1 , but returned to background levels during the following 24 h period. Conclusions NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose...

HLA typing of 86 patients with Graves' disease was performed for the A, B, C and D series antigens. An increased frequency of HLA-B8 (47 per cent) and Dw3 (51 per cent) compared with controls (23.7 and 21 per cent, respectively) was observed. The increase of B8 and Dw3 was almost exclusively found in a group of 48 patients with relapse of disease, whereas the frequency of B8 and Dw3 in patients without relapse did not differ significantly from that of the control group. No association with the presence of exophthalmos, thyroid antibodies, or antibodies to Yersinia enterocolitica serotype 3 could be found.