Table 9. Iron Clearing Efficiency of DFT Analogues Administered to Rodents and Primates with the Respective Log Papp Values.
In the rodents [n = 3 (44), 4 (4 and 48), 5 (DFT, 46, 47, 49), or 8 (26)], the ligands were given po at a dose of 150 μmol/kg (DFT and 4) or 300 μmol/kg (26 and 44, 46–49). The drugs were administered in capsules (44), solubilized in 40% Cremophor RH-40/water (DFT and 4), or given as their monosodium salts, prepared by the addition of 1 equiv of NaOH to a suspension of the free acid in distilled water (26, 46–49). The efficiency of each compound was calculated by subtracting the iron excretion of control animals from the iron excretion of the treated animals. The number was then divided by the theoretical output; the result is expressed as a percent. The relative percentages of the iron excreted in the bile and urine are in brackets.
ICE is based on a 48 h sample collection period.
In the primates [n = 4 (DFT, 4, 46, and 44 in capsules and 47–49), 6 (26), or 7 (44 as the monosodium salt)], the chelators were given po at a dose of 75 μmol/kg (4, 44, 46–49) or 150 μmol/kg (DFT and 26). Ligand 48 was also given to the primates sc at a dose of 75 μmol/kg. The drugs were administered in capsules (44), solubilized in 40% Cremophor RH-40/water (DFT and 4), or given as their monosodium salts, prepared by the addition of 1 equiv of NaOH to a suspension of the free acid in distilled water (DFT, 4, 26, 44, 46–49). The efficiency was calculated by averaging the iron output for 4 days before the drug, subtracting these numbers from the 2 day iron clearance after the administration of the drug, and then dividing by the theoretical output; the result is expressed as a percent. The relative percentages of the iron excreted in the feces and urine are in brackets.
Data are expressed as the log of the fraction in the octanol layer (log Papp); measurements were done in TRIS buffer, pH 7.4, using a shake flask direct method.
The performance ratio (PR) is defined as the mean ICEprimates/ICErodents.