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.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA. bergeron@mc.cop.ufl.edu
Weimar
W R
WR
Wiegand
J
J
D000284:Administration, Oral; D000818:Animals; D002428:Cebus; D004095:Dihydropyridines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D007502:Iron Chelating Agents / Q000493:pharmacokinetics*; D012709:Serum Albumin / Q000378:metabolism; D013844:Thiazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D012709:Serum Albumin; D013844:Thiazoles; C113558:desmethyldesferrithiocin; C050223:desferrithiocin