The origin of the differences in (R)- and (S)-desmethyldesferrithiocin. Iron-clearing properties.
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 FeIII [(S)-DMDFT]2 clearance 6.8 times greater than that of FeIII [R-DMDFT]2. In all primates studied FeIII [(R)-DMDFT]2 in the plasma exceeded 25 mg/L (50 microM) for several hours and remained above 10 mg/L (20 microM) at 8 h while levels of FeIII [(S)-DMDFT]2 never exceeded 50 microM and were at or below the limits of detection 8 h post-injection.
Department of Medicinal Chemistry, University of Florida, Gainesville 32610, USA. bergeron@mc.cop.ufl.edu
R J
RJ
Bergeron
J
J
Wiegand
K
K
Ratliff-Thompson
W R
WR
Weimar
D000818:Animals; D002428:Cebus; D003605:D-Amino-Acid Oxidase / Q000378:metabolism; D003676:Deferoxamine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; C113558:desmethyldesferrithiocin; D007501:Iron; D003605:D-Amino-Acid Oxidase; D003676:Deferoxamine