Abstract
The bioavailability of two scarcely soluble hypolipidemic compounds, 1-O-[p-(myristyloxy)-α-methylcinnamoyl] glycerol (LK-903) and its free acid (LK-A : the parent compound), was evaluated in beagle dogs by determining plasma levels by means of thin-layer chromatography (TLC) scanning densitometry. Following oral administration of LK-903, the main chemical species in plasma were acylated forms in which natural fatty acid (s) was incorporated, while unchanged and hydrolyzed forms represented minor fractions. LK-A showed very poor bioavailability in solid formulations, but exhibited plasma levels comparable to those obtained with LK-903 in solubilized formulations. Intravenous ingestion of LK-903 or LK-A resulted in no detectable transformation to the acylated forms, whereas administration of authentic sample of mono- or diacylated LK-903 produced considerable amounts of LK-903 and LK-A in the plasma, indicating the occurrence of hydrolysis in the systemic circulation. On the basis of these findings, the mechanisms of intestinal absorption were supposed to resemble that of fat absorption, in which solubilization by bile acids and transacylation in the intestinal mucosa may play important roles. In relation to these absorption mechanisms, it is possible to compare the effect of chemical modification with the glyceride moiety with that of pharmaceutical modification of the dosage form for the parent compound.
