Investigation of intestinal absorption of pyridinones in rat

Recently, it has been shown that a number of hydroxypyridinones such as l,2-dimethyl-3-hydroxypyridin-4-one [L1] are useful for the treatment of iron overload in place of desferrioxamine in thalassaemic patients. In this study, the intestinal absorption [I.A.] of L1 and one of its analogues namely 2-methy-3-hydroxypyridin-4-one [L2], which possesses a higher partition coefficient [K[part]] than LI, have been determined. The ligands L1 and L2, used in the present study, were synthesized from maltol and methylamine or ammonia, respectively in a three step reaction method. Identification and purity of compounds were achieved by spectroscopy and elemental analysis. The I.A. of drugs was determined using the Everted Gut Sac method at different concentrations and time intervals. The concentrations of samples were measured by a UV/Vis spectrophotometer [lamda[max]=280 nm]. The results showed that the rate and I.A. of L2 are not statistically different from those of L1. At a concentration of 60 mg/lit, and after 45 min, the absorption reached a maximum for both ligands. It is clear that for the prediction of I.A. of a new drug a simple measurement of K[part] is not sufficient and other factors such as the number of hydrogen bonds between drug molecules and the surrounding molecules should also be taken into account due to their possible interferences. It could be concluded that from the point of I.A, the drug L[2] has no advantage over the L[1]

Comparison of automated continuous flow method with shake-flask method in deterimining partition coefficients of bidentate hydroxypyridinone ligands

The partition coefficients [Kpart, in octanol/water system] of a range of bidentate ligands containing the 3-hydroxypyridin-4-one moiety were determined using shake flask and automated continuous flow methods [filter probe method]]. The shake flask method was used for extremely hydrophilic or hydrophobic compounds with a Kpart values greater than 100 and less than 0.01. For other ligands which possess moderate lipophilicity [Kpart values between 0.01-100] the filter probe method was used. Also the partition coefficient of four ligands with moderate lipophilicity was determined by shake flask method in order to check comparability of these two methods. While the shake flask method was able to determine either extremely hydrophilic or hydrophobic compounds efficiently, the filter probe method was unable to measure such Kpart values. Although, determination of the Kpart values of all compounds is possible with the classical shake-flask method, the procedure is time consuming. In contrast, the filter probe method offers many advantages over the traditional shake-flask method in terms of speed, efficiency of separation and degree of automation. The shake-flask method is the method of choice for determination of partition coefficients of extremely hydrophilic and hydrophobic ligands