BIODISTRIBUTION OF SYNTHETIC THYMOSIN BETA(4) IN THE SERUM, URINE, AND MAJOR ORGANS OF MICE

Thymosin beta(4) (T beta(4)) is a peptide of 43 amino acids that was f irst isolated from the thymus gland and subsequently found to be ubiqu itous in nature. T beta(4) functions mainly as an actin-sequestering m olecule in nonmuscle cells, where its primary role is to maintain the large pool of unpolymerized G-actin in the cell. Studies on the pharma cokinetics of T beta(4) in human and other mammals have not been repor ted so far. In the present study, we have measured T beta(4) concentra tions in serum, urine, and 10 major organs of female Swiss-Webster mic e following intraperitoneal administration of 400 mu g synthetic T bet a(4). Using a modified enzymatic immunoassay, our data show a signific ant increase of T beta(4) in serum starting 2 min after injection and lasting for 40 min (average: 2.34 +/- 0.54 mu g/ml). High concentratio ns were found in urine (59.3 +/- 7.54 mu g/ml) at three different time points after injection (20 min, 40 min, and 2h). Of the 400 mu g T be ta(4) administered to mice 83% was recovered at the end of the study, 44.6% of which corresponded to urine, 1.4% to serum, and 37.5% to the organs. In 50% of the tested organs, the wet weight concentrations of T beta(4) increased significantly from the first 40min to 2 h after in jection in comparison to their baseline wet weight concentrations. The se organs were: the brain (72 mu g/g vs 42 mu g/g), heart (80 mu g/g v s 37 mu g/g), liver (15 mu g/g vs 9 mu g/g), kidneys (65 mu g/g vs 28 mu g/g, and peritoneal fat (47 mu g/g vs 13 mu g/g). Wet weight concen trations increased in the thymus (196 mu g/g vs 147 mu g/g) and muscle (45 mu g/g vs 0 mu g/g) after 6 h of injection. The spleen showed an increase in wet weight concentrations at the 2 min timepoint (267 mu g /g vs 161 mu g/g). Ovaries had a biphasic increase at 40 min(72 mu g/g vs 62 mu g/g) and 24h (92 mu g/g vs 62 mu g/g) after T beta(4) admini stration. In lungs, the highest wet weight increase after injection (1 49 mu g/g at timepoint 6h) was not higher than its basal wet weight co ncentration (153 mu g/g). These pharmacokinetic studies of T beta(4) i n mice have established that high levels of T beta(4) are found in the blood following I.P. administration and the kidney rapidly removes th e peptide from the circulation. The kinetics of this response should h elp define the proper scheduling of administration of T beta(4) during clinical trials in disorders, such as the acute respiratory distress syndrome (ARDS), associated with actin toxicity. (C) 1997 Internationa l Society for Immunopharmacology.