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The Origin of the Differences in ( R )‐ and ( S )‐Desmethyldesferrithiocin: Iron‐Clearing Properties a
Author(s) -
BERGERON RAYMOND J.,
WIEGAND JAN,
RATLIFFTHOMPSON KATIE,
WEIMAR WILLIAM R.
Publication year - 1998
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1998.tb10476.x
Subject(s) - pharmacokinetics , toxicity , chemistry , clearance , pharmacology , plasma clearance , enantiomer , toxicokinetics , chelation , stereochemistry , biology , medicine , inorganic chemistry , urology , organic chemistry
A bstract : The iron clearance properties, toxicity, and pharmacokinetics of ( R )‐ and ( S )‐desmethyldesferrithiocin (DMDFT) are described. The studies were performed in rodent and primate models. While both enantiomers were found to be effective iron chelators with minimal toxicity in the rodents, only ( S )‐DMDFT was able to induce the clearance of any iron in the primates. In addition, two out of nine of the monkeys given ( R )‐DMDFT died within 24 h of drug administration. The reason for the differences in iron clearance properties and the apparent toxicity of the ( R )‐enantiomer in the primates is likely related to the disparities in the pharmacokinetics of the two analogues. The pharmacokinetic data suggest enantioselectivity in renal clearance of the desferrithiocins and their iron complexes with ( S )‐DMDFT clearance 3.5 times greater than that of ( R )‐DMDFT, and Fe III [( S )‐DMDFT] 2 clearance 6.8 times greater than that of Fe III [R‐DMDFT] 2 . In all primates studied Fe III [( R )‐DMDFT] 2 in the plasma exceeded 25 mg/L (50 μM) for several hours and remained above 10 mg/L (20 μM) at 8 h while levels of Fe III [( S )‐DMDFT] 2 never exceeded 50 μM and were at or below the limits of detection 8 h post‐injection.