The Origin of the Differences in (R)‐ and (S)‐Desmethyldesferrithiocin: Iron‐Clearing Properties^a

Abstract

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.

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

“…45,46 Analytical separation was performed on a Discovery RP Amide C 16 HPLC system with UV detection at 310 nm as discussed previously. 63,64 Mobile phase and chromatographic conditions were as follows: solvent A, 5% CH 3 CN/95% buffer; solvent B, 60% CH 3 CN/40% buffer.…”

“…45,46 Analytical separation was performed on a Discovery RP Amide C 16 HPLC system with UV detection at 310 nm as discussed previously. 63,64 Mobile phase and chromatographic conditions were as follows: solvent A, 5% CH 3 CN/95% buffer; solvent B, 60% CH 3 CN/40% buffer.The concentrations were calculated from the peak area fitted to calibration curves by nonweighted least-squares linear regression with Rainin Dynamax HPLC Method Manager software (Rainin Instrument Co.). The method had a detection limit of 0.25 µM and was reproducible and linear over a range of 1-1000 µM.…”

Metabolically programmed iron chelators

“…The supernatant was diluted with H 2 O, vortexed, and filtered with a 0.2 µm membrane. Analytical separation was performed on a Supelco Discovery RP Amide C16 HPLC system with UV detection at 310 nm as described previously [47,80]. Mobile phase and chromatographic conditions were as follows: solvent A, 5% CH 3 CN/95% buffer (25 mM KH 2 PO 4 + 2.5 mM 1-octanesulfonic acid, pH 3.0); solvent B, 60% CH 3 CN/40% buffer.…”

“…The supernatant was diluted with 95% buffer (25 mM KH 2 PO 4 , pH 3.0)/5% CH 3 CN, vortexed, and filtered with a 0.2 µm membrane. Analytical separation was performed on a Supelco Ascentis Express RP-Amide HPLC system with UV detection at 310 nm as described previously [47,80]. Mobile phase and chromatographic conditions were as for 8 .…”

Chelator‐induced iron excretion in iron‐overloaded marmosets

“…uptake, pools, fluxes and excretion patterns ( Finch & Huebers, 1982; Finch et al , 1978 ). This may explain why some compounds that were identified as orally active in rodents, later failed to be effective in non‐human primates ( Bergeron et al , 1998a ) and in patients ( Grady et al , 1994 ). To avoid this and in order to identify the best drug candidates for the expensive and time‐consuming toxicity studies and clinical trials, a monkey model using iron‐overloaded Cebus apella was developed a few years ago ( Wolfe et al , 1989 ; Bergeron et al , 1991 ).…”