Studies on an Oral Iron Chelator: 1,2-Dimethyl-3-hydroxy-pyrid-4-one (DMHP). Mechanism of Intestinal Absorption in Rabbits

Abstract

Abstract Over the last 30 years, desferrioxamine has been the only iron chelator in clinical use. This chelator is expensive and must be given by injection. A new class of chelators, namely 1-alkyl-2-methyl-3-hydroxypyrid-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 the mechanism of intestinal absorption of this new class of drug, using an in-situ system of the intestine from rabbit. The major site of DMHP absorption is in the intestine and is linear with increasing drug concentration. DMHP absorption per unit length of jejunum and ileum is similar; however, due to the larger surface area of jejunum, the absorption by ileum segment is more effective per unit surface. l-Proline, l-tryptophan (amino acids), 2-deoxyglucose, and sodium iodoacetate (metabolic inhibitors) have no effect on DMHP absorption, but l-phenylalanine, 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 passive diffusion based on the linear relationship found between drug concentration and absorption. However, the inhibitive effect of l-phenylalanine suggests that the co-existence of a facilitated uptake cannot be ruled out.