Dose-linear pharmacokinetics, tissue distribution, and excretion of a recombinant fusion protein 125I-GST-TatdMt possessing potent anti-obesity activity

Abstract

This study first examined the pharmacokinetic disposition of GST-TatdMt, a recombinant Tat protein possessing potent anti-obesity activity, in rats after i.v. injection. GST-TatdMt was over-expressed in E. coli, purified, and radioiodinated using the IODO-GEN method. The radioiodinated 125I-GST-TatdMt was administered to rats at doses of 9 μg (1640 nCi), 18 μg (3388 nCi), and 35 μg (6420 nCi). Upon administration, the total radioactivity in serum declined bi-exponentially, with the average terminal elimination half-life ranging from 13.7 to 15.7 h. There was a linear relationship between dose and AUC INF ( r 2=1.000) and between dose and Co ( r 2=0.999). The fraction of administered radioactivity excreted in feces was low (mean range 1.5–2.8%), while the majority of the radioactivity was excreted in urine (mean range 54.9–61.4%). The radioactivity found in the liver, lungs, spleen, and kidneys were higher than in serum, but the tissue-to-serum ratios were relatively low (<1.64). The radioactivity in testes, adipose tissue, heart, and brain was lower than in serum (tissue-to-serum ratios 0.046–0.27). The findings of this study indicate dose-linear pharmacokinetics of 125I-GST-TatdMt in rats over the i.v. dose range studied.