Abstract
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.
Footnotes
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Send reprint requests to: Raymond J. Bergeron, Ph.D., Box 100485 JHMHC, Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610. E-mail: bergeron{at}mc.cop.ufl.edu
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This study was supported by National Institutes of Health Grant DK 49108.
- Abbreviations used are::
- DFO
- desferrioxamine B
- DFT
- desferrithiocin
- RE
- reticuloendothelial
- DMDFT
- desmethyldesferrithiocin
- 4-(S)-hydroxydesazaDMDFT
- (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-thiazolecarboxylic acid
- desazaDMDFT
- 2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid
- AUC
- area under the time-concentration curve
- AUMC
- the total area under the first-moment curve
- MRT
- mean residence time
- CLR
- renal clearance
- Received June 17, 1999.
- Accepted August 18, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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