Abstract
An attempt was made to determine and compare oral absorption characteristics of ester derivatives of pyrithioxin (I) filled in hard gelatin capsules after administration to dogs. Ester derivatives of I studied were pyrithioxin-tetraacetate dihydrochloride (I-A·2HCl), pyrithioxin-tetrapropionate dihydrochloride (I-P·2HCl), pyrithioxin-tetra-n-butyrate dihydrochloride (I-B·2HCl), and pyrithioxin-4, 4'-disuccinate dihydrochloride (I-S·2HCl). Blood concentrations of 5'-desoxy-5'-methylsulfinylpyridoxol (II) and urinary excretions of metabolites of I were studied following oral administration of esters. The values of area under the blood concentration-time curve (AUC) and total urinary excretion in terms of mole percent of dose were used as provisional bioavailabilities of the ester and compared with those of I·2HCl. The bioavailability of I-P·2HCl significantly increased with the maximum blood concentration 1.63 times larger and the total urinary excretion 1.47 times larger than those of I·2HCl. There appeared to be a close relationship between the improved bioavailability of I-P·2HCl and its large partition coefficients of n-octanol/pH 6.5 buffer. The insufficient bioavailability of I-S·2HCl appeared to be closely correlated with its low partition coefficient of 0.094 and incomplete hydrolysis of ester during absorption. The esters were considered to be hydrolyzed in intestinal fluid and/or in the intestinal membrane and the parent drug, I, permeated through the intestinal tract. The uptake of 14C-labelled glucose into the brain of the mouse was preliminary studied with I-A·2HCl and I-S·2HCl. I-A·2HCl indicated a significant increase of glucose through the blood-brain barrier similar to that of I·2HCl, but not with I-S·2HCl.
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