Taiji Nakayama

Enhancing effect of 1-dodecylazacycloheptan-2-one (Azone) on the absorption of salicylic acid from keratinized oral mucosa and the duration of enhancement in vivo

Abstract Enhancing effect of the pretreatment with 1-dodecylazacycloheptan-2-one (Azone) on the absorption of salicylic acid from keratinized oral mucosa was investigated in vivo using a hamster cheek pouch. The absorption was significantly increased after the 4 h pretreatment with Azone-emulsion when the pretreatment medium contained Azone above 0.2%. The enhancement was observed at all pH conditions examined irrespective of the degree of dissociation of the drug. The apparent disappearance rate constant of salicylic acid, calculated from the time course of the sum of remaining amounts of the drug in both the luminal fluid and the tissue, in Azone-pretreated cheek pouch was approximately 2.7 times larger than in the non-treated one. The pharmacokinetic analysis of the plasma concentration of salicylic acid after the intra-cheek-pouch administration revealed that Azone pretreatment enhanced the absorption i.e., increased the absorption rate constant and shortened the mean absorption time by one-fifth, and brought the peak plasma concentration approximately twice higher. The enhanced absorption after 1 h pretreatment with 5% Azone-emulsion diminished with the lapse of time and the barrier function of the cheek pouch was completely recovered within 6 h after the removal of the Azone-emulsion.

Regional Variation in Oral Mucosal Drug Absorption: Permeability and Degree of Keratinization in Hamster Oral Cavity

The regional permeability of oral mucosa to salicylic acid was investigated in vivo in hamsters along with histological variations, especially the degree of keratinization. Histological sections from six regions, i.e., sublingual mucosa, buccal mucosa, dorsum of tongue, ventral surface of tongue, labial mucosa, and cheek pouch mucosa, were prepared to assess the degree of keratinization. The area under the plasma concentration–time curve of salicylic acid following the administration of salicylic acid to the oral mucosa with a film dosage form and the thickness of stratum corneum of each site were in inverse proportion to each other, suggesting that the stratum corneum layer represents the principle barrier to drug absorption.

Effects of surfactants on the absorption of salicylic acid from hamster cheek pouch as a model of keratinized oral mucosa

Abstract The effect of surfactants on the absorption of salicylic acid from keratinized oral mucosa was investigated by hamster cheek pouch method in vivo at pHs 3.0, 4.0 and 7.0. Four surfactants, sodium laurylsulfate (SLS), cetylpyridinium chloride (CPC), polysorbate 80 (PS-80) and sodium taurocholate (STC), were examined as adjuvants. The interaction between salicylic acid and each surfactant was determined by the molecular sieve method using Sephadex G-25. Decreased absorption of salicylic acid by the presence of PS-80 was observed in the lower pH conditions and this phenomenon was explained by the decrease in the free fraction of salicylic acid. The absorption of salicylic acid in the presence of ionic surfactants, SLS or CPC, was much larger than that predicted by the loss of activities which was caused by the interaction between the surfactant and the drug molecule. Pretreatment with SLC or CPC brought the salicylic acid absorption to increase in all pH conditions examined and the effects were dependent on the surfactant concentration. STC and no effect on the absorption. The mechanisms of the effects of ionic surfactants on the permeability of keratinized oral mucosa were discussed.

Use of lipid disperse systems in transdermal drug delivery: Comparative study of flufenamic acid permeation among rat abdominal skin, silicon rubber membrane and stratum corneum sheet isolated from hamster cheek pouch

Abstract The characteristics of in vitro permeation of flufenamic acid (FA) from lipid disperse systems composed of phosphatidylcholine (PC) and glycosylceramide (GC) were compared among rat abdominal skin, a silicon rubber membrane (Silastic ® ) and a stratum corneum (SC) sheet isolated from hamster cheek pouch. When a PC dispersion (PCD) containing 20 μmol PC/ml was applied, the permeation of FA through rat skin was enhanced approx. 2.2-fold compared with that from the lipid-free suspension (LFS). Further, a nearly 2-fold enhancement was observed when a GC-containing PCD (10% GC-PCD) was examined. A similar pattern of enhancement could be reproduced when cheek pouch SC was used instead of, rat skin, whereas it was not observed in Silastic ® . The enhanced permeation in the skin could not be explained on the basis of the incremental increase in the apparent solubilities. A significant correlation was observed between skin permeation and epidermal tissue uptake of FA from LFS and PCDs, although the nearly 2-fold increase found in 10% GC-PCD might be due to mechanisms other than the increase in epidermal tissue uptake. The usefulness of an SC sheet isolated from hamster cheek pouch, a new model membrane without appendages, in studying the direct action of either permeation enhancers or dosage forms designed to enhance the percutaneous permeation of drugs on the SC is discussed.

Existence of a specialized absorption mechanism for cefadroxil an aminocephalosporin antibiotic, in the human oral cavity

Abstract The absorption of cefadroxil, an aminocephalosporin antibiotic, from the oral cavity of healthy volunteers was examined. The buccal absorption test for cefadroxil at varying concentrations demonstrated the phenomenon of saturation in absorption behavior. Furthermore, absorption of cefadroxil was inhibited by the presence of another aminocephalosporin, cephalexin, but not by the structurally unrelated sulfisoxazole. The results suggest that aminocephalosporin antibiotics are absorbed from the human oral cavity via a specialized transport mechanism. On the other hand, cefadroxil absorption from hamster cheek pouch mucosa, a keratinized oral mucosa, took place in proportion to the initial concentration and was not influenced by the presence of cephalexin, indicating that the physicochemical interaction between these two aminocephalosporins in the luminal solution of the keratinized oral mucosa is practically negligible. Thus, the localization of the specialized absorption mechanism for cefadroxil was strongly suggested to be in the non-keratinized region in the human oral cavity.

Biopharmaceutical Evaluation of Salicylazosulfanilic Acid as a Novel Colon-Targeted Prodrug of 5-Aminosalicylic Acid

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.

Pollycyclic N-Hetero Compounds. XXXI. Synthesis and Anti-platelet Aggregation Activity of 4-Substituted 5,6-Dihydrobenzo[h]quinazolines

Title compound were synthesized by the reaction of 4-chloro-5,6-dihydrobenzo[h]-quinazoline with amines

Colonic mucosa-specific “pro-antedrugs” for oral treatment of ulcerative colitis: design, synthesis and fate of methyl 20-glucopyranosyloxyprednisolonates

Abstract Hydrophilic steriod derivatives, methyl 20-β-glucopyranosyloxyprednisolonates (15 and 16), were synthesizd from prenisolone via methyl 20( R/S )-dihydroprednisolonates (2 and 1) based on a novel colonic mucosa-specific drug delivery system. Optimal conditions for the syntheses of each isomer 1 and 2 were found by the extensive studies on the reaction rates from prednisolone under various concentrations of cupric acetate in dry methanol. Their configurations at C-20 in compounds 1 and 2 were determined by their formation mechanism. The fate of compounds 15 and 16 after the oral administration was examined in rats ang guinea-pigs. The glycosides were stable in the small-intestinal contents, but the glycoside bonds were cleaved by the action of bacteria in the large-intestinal contents to release compounds 1 and 2, respectively, which were rapidly hydrolysed to the inactive carboxylates in the plasma. The high recovery of the glycosides and the aglycons in the large-intestinal contents after intrajejunal administration of compounds 15 and 16 may be orally effective ‘pro-antedrugs’, which specifically express the anti-inflammatory acitivity in the glycosides 15 and 16 may be orally effective ‘pro-antedrugs’, which specifically express the anti-inflammatory activity in the colonic mucosa with no systemic effect.

Biopharmaceutical studies on drug/conjugated-metabolite interactions. II. Effect of acetaminophen sulfate on pharmacokinetics of acetaminophen in rats

The effect of conjugated-metabolite, acetaminophen sulfate (APAPS), on the pharmacokinetics of its parent drug, acetaimnophen (APAP), was examined in rats. Following the i.v. bolus administration of APAP with APAPS, the plasma elimination of APAP was delayed and the distribution volume of APAP was increased at the APAPS coadministration with 60 mg APAP equivalent per kg (eq/kg). The percentages of dose excreted in the urine and bile in 4 h as APAP and its conjugated metabolites, APAPS and acetaminophen glucuronide, were significantly decreased. On the other hand, following the i.v. bolus administration of APAP under the steady-state concentration of APAPS, the distribution volume and total body clearance of APAP were significantly increased. Competitive displacement in serum protein binding of APAP by APAPS was ascertained in vitro and in vivo. A part of the conflict between the bolus and infusion experiment may be explained by the changes in the distribution volume of APAP contributed to the APAPS concentration-dependent serum protein binding of APAP. It was speculated that the pharmacokinetics of APAP was partly interacted with APAPS by the displacement of serum protein binding.

Biopharmaceutical studies on drug/conjugated-metabolite interactions. I. Fate of acetaminophen sulfate, a major conjugated metabolite of acetaminophen, in rats

Abstract The plasma elimination kinetics and intestinal absorption kinetics of acetaminophen sulfate (APAPS), a major conjugated metabolite of acetaminophen (APAP), indispensable for the kinetic elucidation of drug/APAPS interactions, were examined in rats. Plasma elimination kinetics of APAPS after i.v. administration could be described by a two-compartment model with linear parameters to the dose. The deconjugation of intravenously administered APAPS, i.e., the formation of APAP, was recognized in neither plasma, urine nor bile. Approx. 80% of intravenously administered APAPS was excreted as the unchanged form in the urine in 4 h while biliary excretion was only a few percent of the dose. Plasma profiles of APAPS after oral administration showed two peaks, but the second one disappeared when the rat was pretreated with kanamycin sulfate. However, APAPS permeation through the small- and the large-intestinal walls determined in situ was not altered after kanamycin treatment. High APAPS-hydrolyzing activities present in the cecal and colonic contents and the feces, but not in the small-intestinal contents, completely disappeared after kanamycin treatment. Thus, part of the orally administered APAPS was absorbed as the unchanged form from both the small and large intestines, and considerable amounts of the remainder were absorbed from the large intestine as APAP after enzymatic hydrolysis by the intestinal microflora during transit through the lower bowel.