Kazutaka Higaki

Enhanced Membrane Permeability to Phenol Red by Medium-Chain Glycerides: Studies on the Membrane Permeability and Microviscosity

To clarify the mechanism of the drug absorption enhancement by medium-chain glycerides (MCG), the changes in membrane permeability provoked by MCG were investigated with liposomal uptake experiments. Uptake of phenol red (PR) into liposomes increased with an increase in MCG content in the liposomal membrane, suggesting that PR absorption was enhanced in the “transcellular route.” However, the apparent membranous microviscosity obtained in fluorescence depolarization studies tended to increase with the addition of MCG in both the hydrophobic core and the polar head regions of the liposomal membrane. Thus, an enhancement in membrane permeability caused by MCG was not accompanied by a decrease in the apparent membranous microviscosity.

Effect of medium-chain glycerides on the intestinal absorption and the hepatobiliary transport of Phenol red

Abstract The effects of medium-chain glyceride (MGK) on the intestinal absorption and the hepatobiliary transport of Phenol red (PR) were investigated in rats. The in situ recirculation experiment using the small intestine showed that disappearance of PR from the recirculated MGK emulsion at a lipid content of 4% was over 5 times greater than that from the buffer solution, although the effect diminished with the increase of the lipid content. On the contrary, in the everted sac experiments, mucosal to serosal transport of PR from MGK emulsion was reduced to about one half of the control, and the pretreatment with PR-free MGK emulsion could not enhance PR disappearance from the buffer solution recirculated successively. The effect of a polyoxyethylene derivative of castor oil (HCO-100) employed for emulsion preparation on the transport of PR was investigated by the everted sac experiments. The amount of PR transported was decreased with the increase of HCO-100 in the range of 0.1–2.0%. These results may suggest that other factors are related with the promoting effect except for the membrane permeability. When the absorption of MGK components was examined by in situ and in vitro studies, the disappearance of MGK components in the former was nearly twice of that in the latter. The inhibiting effect of MGK on the biliary excretion of PR was observed in the in situ recirculation study with MGK emulsion containing PR. The biliary excretion percent of PR was also significantly reduced by injecting the components of MGK into the mesenteric vein.

Transmucosal passage of liposomally-entrapped drugs in rat small intestine.

Intestinal absorption of liposomally-entrapped drugs was investigated for egg yolk phosphatidylcholine-cholesterol (2:1 by molar ratio) liposomes (EggPC liposome) and distearoylphosphatidylcholine-cholesterol (2:1) liposomes (DSPC liposome). The release of carboxyfluorescein, an aqueous phase marker, induced by the presence of everted rat intestine was 40 % and 6 % in one hour from DSPC liposomes and EggPC liposomes, respectively, and it is suggested that EggPC liposomes are more stable in the intestinal lumen. The transport of a liposomally-entrapped drug was examined with fluoresceinisothiocyanate-conjugated dextran (FITC-D) as a model drug that has a small mucosal-to-serosal clearance because of its high average molecular weight (64200). The clearance of FITC-D entrapped in DSPC liposomes was largely reduced and could be accounted for by the clearance of the extraliposomal FITC-D concentration in the preparation. On the other hand, the calculated clearance of EggPC liposome-associated FITC-D was similar to or even higher than that of free FITC-D. The serosal appearance of the EggPC liposome-associated drug was inhibited by colchicine, cytochalasin B, and iodoacetate, suggesting that the liposome was incorporated into the epithelial cells by endocytosis. However, the observation that a lipid phase marker, 14C-dipalmitoylphosphatidylcholine, failed to be transported into the serosal fluid indicates the absence of the penetration by an intact liposomal form.