PHARMACOKINETICS OF FEXOFENADINE IN THE SETTING OF DYSFUNCTION OF THYROID GLAND

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Purpose of the work was to investigate a pharmacokinetics of fexofenadine - marker substrate of carrier protein of glycoprotein-P in the setting of thyroid gland dysfunction. Materials and methods of the study: we carried out the work using 24 female chinchilla rabbits weighed 3200±200 g. Hyperthyroidism was modeled by the percutaneous injection of thyroxin at doses 25 (n=6) and 100 µg/kg of the weight (n=6) during 14 days. Hyperthyroidism was simulated by using thiamazole injection at doses 2.5 (n=6) and 5 mg/kg (n=6) of the weight during 21 day. Before the experiment start, on the 14 and 21 day after the injection of the drugs to animals per os, fexofenadine was injected at dose 30 mg/kg of the weight and then took a blood sample from the auricular vein. Concentration of fexofenadine in blood serum was determined by using the method of HPLC. Fexofenadine was not exposed to metabolism and its pharmacokinetics only depends on the function of carrier protein of glycoprotein-P, which prevents its adsorption into intestines and conduces its excretion with bile (90%) and urine (10%). We determined the concentration of T3, T4, and TTG in blood serum by using radio-immune method. The results obtained were processed with ANOVA, repeated measurements, and Newman- Keuls test. Results: percutaneous injection of thiamazole to rabbits at doses 2.5 and 5 mg/kg of the weight during 21 days led to the expansion of experimental hyperthyroidism which was characterized by an elevated level of T3 and T4 and TTG concentration rise in blood serum. The expansion of the experimental hyperthyroidism provoked the reduction of Сmax, AUC0-t, MRTt (thyroxin doses 25 and 100 µg/kg) and the rise of general clearance (thyroxin dose 100 µg/kg) fexofenadine, which showed its reduction in the organism, accelerated injection, and functional activity of carrier protein glycoprotein-P augmentation. Peroral administration of thiamazole to rabbits at doses 2,5 and 5 mg/kg of the weight during 21 days led to the expansion of hypothyroidism which was characterized by the reduction of T3 and T4 levels with TTG concentration augmentation in blood serum on the 14th, 21st day of thiamazole appliance and on the 5th day of the drug cancellation. The development of the experimental hypothyroidism provoked the augmentation of Сmax of fexofenadine on the 14th, 21st days of thiamazole administration, and on the 5th day of its cancellation (doses 2.5 and 5 mg/kg). On the 5th day of thiamazole cancellation we saw the augmentation of Cmax, AUC0-t, AUC0-∞, MRT and the reduction of the general clearance (dose 5 mg/kg) of fexofenadine. The data about the change of pharmacokinetic parameters of fexofenadine showed its accumulation in rabbits organisms, slowing down of its excretion, and respectfully about the reduction of the functional activity of glycoprotein-P. Conclusions: 1) expansion of the experimental hyperthyroidism is accompanied with the reduction of fexofenadine content in an organism and its accelerated excretion; 2) experimental hypothyroidism leads to the accumulation of fexofenadine in an organism and the slowing down of its excretion.