Pharmacokinetics of orally administered desferrithiocin analogs in cebus apella primates

The pharmacokinetic behavior of three iron chelators based on the desferrithiocin (DFT) pharmacophore, (S)-4, 5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (desmethyldesferrithiocin, DMDFT, 2); (S)-4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-thiazolecarboxylic acid [4-(S)-hydroxydesazaDMDFT, 3); and (R)-2-(2-hydroxyphenyl)-4-oxazolinecarboxylic acid, the oxazoline analog of desazaDMDFT, 4, is described. Although 2 and 3 are comparably effective in inducing iron excretion upon oral administration, they exhibit markedly different plasma pharmacokinetics. Ligand 2 achieves a substantially higher plasma concentration than does 3, yet the renal clearance of these compounds is similar. The oxazoline analog 4 shows poor iron clearance when administered orally, although it remains in the plasma for extended periods. Chelator 4 demonstrates a marked capacity to bind to human serum albumin compared with the thiazoline derivatives. The possible implications for designing ligands for the treatment of transfusional iron overload are discussed.