STUDIES ON AN ORAL IRON CHELATOR - 1,2-DIMETHYL-3-HYDROXY-PYRID-4-ONE(DMHP) - MECHANISM OF INTESTINAL-ABSORPTION IN RABBITS

Over the last 30 years, desferrioxamine has been the only iron chelato r in clinical use. This chelator is expensive and must be given by inj ection. A new class of chelators, namely 1-alkyl-2-methyl-3-hydroxypyr id-4-ones, have been shown to be orally effective. Using 1,2 dimethyl- 3-hydroxy-pyrid-4-one (DMHP), we have carried out a study to clarify t he mechanism of intestinal absorption of this new class of drug, using an in-situ system of the intestine from rabbit. The major site of DMH P absorption is in the intestine and is linear with increasing drug co ncentration. DMHP absorption per unit length of jejunum and ileum is s imilar; however, due to the larger surface area of jejunum, the absorp tion by ileum segment is more effective per unit surface. L-Proline, L -tryptophan (amino acids), 2-deoxyglucose, and sodium iodoacetate (met abolic inhibitors) have no effect on DMHP absorption, but L-phenylalan ine, an amino acid with a 6-member carbon ring, significantly inhibits the DMHP absorption from the intestinal segment. We conclude that the mechanism of DMHP absorption in the intestine is mainly by simple pas sive diffusion based on the linear relationship found between drug con centration and absorption. However, the inhibitive effect Of L-phenyla lanine suggests that the co-existence of a facilitated uptake cannot b e ruled out.