Pharmacokinetics of orally administered desferrithiocinn analogs in Cebus apella primates

The pharmacokinetic behavior of three iron chelators based on the desferrit hiocin (DFT) pharmacophore, (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolec arboxylic 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 analo g of desazaDMDFT, 4, is described. Although 2 and 3 are comparably effectiv e in inducing iron excretion upon oral administration, they exhibit markedl y different plasma pharmacokinetics. Ligand 2 achieves a substantially high er plasma concentration than does 3, yet the renal clearance of these compo unds is similar. The oxazoline analog 4 shows poor iron clearance when admi nistered orally, although it remains in the plasma for extended periods. Ch elator 4 demonstrates a marked capacity to bind to human serum albumin comp ared with the thiazoline derivatives. The possible implications for designi ng ligands for the treatment of transfusional iron overload are discussed.