FIG. 5.
Small molecule-induced T4 secretion and pharmacokinetics. (A) Male mice (C57BL/6J; n=2 per group) were subjected to intraperitoneal (i.p.) injection of MS437 and MS438 with a single dose of 100 μg per mouse per day using the small molecules emulsified in <50% DMSO and compared with vehicle alone–injected mice for three consecutive days. This figure illustrates the distribution of the individual readings of each mouse from the samples collected after 72 h. The mean of the distribution is indicated by the horizontal bar. When compared to the pre-immune and vehicle-injected controls, both MS437 and MS438 induced an increase in serum total thyroxine (T4) levels after 72 h of treatment (**p<0.01). (B) and (C) Male mice (Balb/c; n=18 per group) were dosed intravenously (i.v.; group I) or i.p. (group II) at 20 mg/kg of body weight. The compounds were prepared in formulation containing DMSO, propylene glycol of Cremphor EL, PEG400, and saline. The dosing volume administered for the i.v. route was 5 mL/kg, and for the i.p. route was 10 mL/kg. Blood samples were collected from three mice at the start and then at each time point of 2, 4, 6, 12, and 24 h (both i.v. and i.p.). The samples were analyzed by mass spectrometry with internal standards. As the T1/2 is calculated from terminal elimination points, it remains the same for both routes of compound injection. Molecule MS437 had a longer serum half-life (3.10 h) compared to MS438 (1.02 h). The difference in strain of mice used for the pharmokinetic study and the T4 release study is based on availability of animals at the time.