The effect of formulations of lecithin-dispersed preparation on the absorption of d-α-tocopherol acetate (VEA) from the small intestine was investigated in rats. When lecithin-dispersed preparations containing VEA or polysorbate 80 (PS-80)-solubilized solution of VEA were intraduodenally administered, VEA was hydrolyzed to d-α-tocopherol (VE) and was not detected in the plasma nor in the thoracic lymph. The maximum plasma concentration (Cmax) of VE after the intraduodenal administration of a preparation consisting of VEA, soybean phosphatidylcholine (PC) and medium-chain triglycerides (MCTG) (VEA/PC/MCTG, 5/16/1 by weight) was highest among the VEA preparations, and PS-80-solubilized solution gave the lowest Cmax. AUC of VE up to 24 h was also increased by the addition of MCTG to VEA/PC preparation. In the thoracic duct-fistula rat, the transport of VE into the thoracic lymph was increased by the administration of the VEA/PC/MCTG preparation significantly more than the VEA/PC preparation ; the cumulative amounts of VE recovered in the thoracic lymph up to 24 h were 23.2±0.5% and 10.9±1.5% of dose, respectively. The plasma concentration of VE was not increased in the thoracic duct-fistula rat even after the intraduodenal administration of VEA preparations, suggesting that VE is not transported directly to the systemic circulation, but by way of the lymphatic route. The lymphatic transport of VE following the intraduodenal administration of VEA/PC/MCTG preparation was markedly diminished by the simultaneous administration of Pluronic L-81 emulsion, an inhibitor of chylomicron formation. It is suggested that the chylomicron is essential to the lymphatic transport of VE from VEA preparations.
A prodrug of 5-aminosalicylic acid (5-ASA), salicylazosulfanilic acid (SASA), which consists of sulfanilic acid linked to 5-ASA through an azo-linkage was newly synthesized. Biopharmaceutical properties of SASA were evaluated in comparison with those of salicylazosulfapyridine (SASP) in rats. Since SASA is much more hydrophilic than SASP, the absorption of SASA from the small intestine was less in comparison with SASP. When SASA and SASP were incubated with the rat intestinal contents under anaerobic conditions, both compounds were stable in the small-intestinal contents, but were rapidly degraded to 5-ASA in the cecal and the colonic contents. The degradation to 5-ASA by the large-intestinal contents was suppressed by the pretreatment with kanamycin sulfate, suggesting that the bioconversion of SASA is mediated by the intestinal microflora similarly to that of SASP and that SASA is also a prodrug of 5-ASA. After the oral administration, 5-ASA was found neither in the stomach nor in the small intestine in case of both prodrugs. Most of the prodrugs were transferred to the lower intestine where they were degraded to 5-ASA. The recovery of SASA including the metabolites from the gastrointestinal tract at four hours after the oral administration was significantly greater than that of SASP. Accordingly, SASA is free from the liberation of sulfapyridine, the adverse effect moiety of SASP, and less absorbable in the small intestine. Thus, the beneficial characteristics of SASA as an excellent colon-targeted prodrug of 5-ASA were clarified.
The maximum fluxes (Jmax) of β-blockers through keratinized membranes were determined in vitro and compared with their physicochemical parameters such as lipophilicity (log k'O) and melting point (mp). Rat abdominal skin and hamster cheek pouch mucosa were used as the model membranes. Propranolol, metoprolol, timolol, pindolol, nadolol and agenolol were used as β-blockers with a variety of physicochemical characters. Linear relations of Jmax with either log k'O or mp were observed both in intact rat skin and in intact hamser cheek pouch, suggesting that the lipophilicity and thermodynamic actitvity of a drug in the crystal state primarily affect the drug's permeation through these membranes.However, the slope, dJmax/d(log k'O), for cheek pouch mucosa was greater than that for rat skin, corresponding to the lack of appendageal shunt pathways in cheek pouch. Penetration studies using the delipidized membranes and the isolated stratum corneum sheet of hamster cheek pouch mocosa clarified that the primary rate-limiting barrier function might exist in the lipid layer of the stratum corneum. Jmax values for the tape-stripped and delipidized skins correlated with both the solubilities of drugs in the vehicle and with the mp, suggesting the polar porous characteristics of both model membranes. However, a theoretical approach confirmed that the contribution of an intracellular or aqueous pore route in the intact membrane to the permeation of drugs with lipophilic indexes is negligible.
Lymphatic transport of lipid-soluble dye, Sudan Blue, and vitamin A acetate from oil-in-water emulsions was investigated using in situ loop method by the rat small intestine. A natural oil, triolein, which was known to be transported mainly through lymphatic pathway, was chosen as an oil phase of the emulsion. Lymphatic transport of Sudan Blue and vitamin A acetate was very small in the absence of bile. When sodium taurocholate and egg phosphatidylcholine were co-administered with emulsions, lymphatic transport of lipid-soluble compounds were recovered even in bile fistula rats. Addition of one of them could not recover completely the lymphatic transport of lipid-soluble compounds. It was concluded that both bile salts and phosphatidylcholine were necessary for the lymphatic transport of the fat and lipid-soluble compound which interact with oil administered intraluminally. However, overall contribution of lymphatic pathway to their disappearance from the small intestinal lumen is very small, and the main route of their absorption is thought to be the portal pathway.
Model lipid mixtures composed of ceramide (40%), cholesterol (25%), palmitic acid (25%) and cholesterol 3-sulfate (10%) were used as the model for intercellular lipids of stratum corneum (SC) to evaluate a barrier function of SC for drug permeation. Six beta-blockers, propranolol, metoprolol, timolol, pindolol, nadolol and atenolol, were used as the model permeants. The maximum flux values (observed flux/thermodynamic activity, Jmax) of drugs through the membrane coated with the model lipid mixtures and two keratinized membranes, rat skin and hamster cheek pouch, were determined in vitro using a Franz-type diffusion cell. Further, drug partition coefficients to the multilamellar liposomes prepared by the model lipid mixtures were determined. The Jmax values obtained in the model lipid-coated membrane, in the intact rat skin and in the intact hamster cheek pouch mucosa, bore a linear relationship to each other. These results suggest that the model lipid-coated membrane is a useful tool for the prediction of the drug permeability through the keratinized membrane in the in vitro system. The Jmax values also correlated with drug partition to the model lipid liposomes, suggesting the validity of the use of the model lipid mixtures as the substitutes for the intercellular lipids of the stratum corneum.
