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The effects of a series of fatty acids on the rectal absorption of propranolol (PL) were examined in vitro, using macrogol 1500 base and rat rectal tissue. Lauric acid, at a fatty acid: PL molar ratio of 1:1, produced the largest increase in permeation rate (Js), penetration coefficient and partition coefficient of PL. PL flux was increased 2.5-fold in the presence of lauric acid compared to that without the fatty acid. However, the Js value of PL was decreased at increased molar ratios (e.g., 3:1) of lauric acid. The permeation rate of lauric acid across the rectal membrane was much larger than that of PL. Furthermore, the apparent partition coefficient of PL in an n-octanol/buffer system was significantly increased at a 1:1 molar ratio to lauric acid compared with that of PL alone. These results suggest that a complex-mediated mechanism facilitates PL transport, thereby partially contributing to the enhancement of PL rectal absorption. A similar mechanism is applicable to percutaneous drug absorption, as reported previously. Thus, a portion of PL, after first forming a complex with fatty acids, may rapidly permeate across rectal membranes.

The sodium salts of the 3, 5-dichloro, 3, 5-dibromo-, 3, 5-diiodo-, and 5-methoxy-analogs of salicylic acid have been evaluated as enhancers of rectal insulin absorption. A relationship was found between adjuvant potency and relative lipophilicity. Maximal adjuvant activity was obtained with 0.1 M 3, 5-dichlorosalicylate. Higher concentrations (0.15 M) of 3, 5-diiodosalicylate produced a decline in adjuvant activity, which may be associated with extraction of specific cellular proteins. This may indicate the existence of an optimal salicylate lipophilicity for adjuvant efficacy. Relative adjuvant activity was found to be related to the lymph : plasma absorption ratio of [125I] insulin. Lymphatic uptake of insulin was not related to lymph flow rate.

The influence of suppository bases and adjuvants on the release rate of drugs and the absorption of non-absorbable drugs such as sulfanilic acid (SA) and sulfaguanidine (SG), was investigated following the rectal administration of suppositories. The suppository bases used were lipophilic bases such as Witepsol W 35, H 15, S 55, E 75 and hydrophilic base such as macrogol. SA was rapidly released from macrogol, W 35, H 15 and S 55, except E 75. On the other hand, SG was rapidly released from macrogol, whereas the release of SG from lipophilic bases was slow. Rectal absorption of SA and SG following administration of each drug alone in suppository form was slight. On the addition of diclofenac sodium (DF) as absorption promoter the blood levels of SA and SG released from all suppositories increased by about two to four fold compared with those suppositories containing only SA or SG, respectively. However, the absorption of SG still did not attain sufficient levels by the administration of DF only. The rectal absorption of SG was markedly increased by the release rate of the drug from the suppository. These results indicate that after administration of these suppositories the bioavailability of non-absorbable drugs was sufficiently improved by enhancing both the release rate from the suppositories and the rectal membrane permeability.

The duration of the absorption-enhancing effect of sodium octanoate (C8), sodium hexanoate (C6) and glyceryl-l-monooctanoate (MO) on the rectal absorption of gentamicin (GM) using the hollow-type suppository was investigated in rabbits. To evaluate the duration of the absorption-enhancing effect by pretreatment (treatment of absorption enhancer before GM administration), suppository I containing each absorption enhancer in the cavity was administered into the rectum. Then suppository II containing GM in the cavity was administered at predetermined times (0.33, 2, 6 and 24 h) after the administration of suppository I. Plasma GM levels obtained by the pretreatment with absorption enhancer were compared with those obtained by the simultaneous administration of GM with absorption enhancer. The AUC and Cmax of GM significantly decreased with the pretreatment of C8 (6 and 24 h), C6 (2 and 6 h) or MO (6 and 24 h) before rectal GM administration, as compared with the simultaneous administration of GM with C8, C6 or MO. A marked decrease in the absorption-enhancing effect of C8, C6 and MO on rectal GM absorption was observed by the prolongation of the period between the pretreatment of each absorption enhancer and GM administration. The duration of the absorption-enhancing effect of C6 was shorter than that of C8, whereas this duration of MO was similar to that of C8. The effect of these absorption enhancers disappeared 24 h after the pretreatment. These results suggested that the lowering of the membrane transport barrier function recovered about one day after the administration of C8 or MO.

Diethylethoxymethylene malonate (DEEMM) and diethyl maleate (DEM) enhanced the rectal absorption of cefmetazole in rats when studies were carried out using in vivo, in situ rectal loop and in vitro rectal everted sac method. Since an increase of cefmetazole transport was found when concentration of nonprotein sulfhydryls in rectal tissue was decreased by the presence of either DEEMM or DEM in the study using in vitro everted sac method and the enhancement of cefmetazole absorption by the coadministration of either DEEMM or DEM was suppressed by the treatment with dimercaprol, membrane permeability of rectal tissue seems to be regulated by the concentration of nonprotein sulfhydryls in rectal tissue. On the other hand, it was also found that there were differences between the action of DEEMM and the action of DEM from the following two results : 1) enhancing action of DEEMM was suppressed by the presence of calcium ion in microenema while action of DEM was not so much influenced, and 2) DEEMM enhanced the rectal absorption of lysozyme in rabbits but DEM did not.

The effect of gel preparation on the rate of absorption of a rectally administered insulin which was suspended in a polyacrylic acid aqueous gel base (0.1%, pH 6.5) was investigated in the alloxan diabetic rats and rabbits. The preparation was administered into the in situ rectal loop in rats or infused directly into the rectum in rabbits, and the change in the blood glucose level and plasma insulin value was taken as a measure to evaluate the rate of rectal absorption of insulin. The blood glucose lowering effect in both rats and rabbits was dose-dependent, namely, a slight effect was observed at 1 IU/kg followed by a significant effect with 3 and 5 IU/kg, and a sharp hypoglycemic effect was recorded with 10 IU/kg which lasted for 5 hr. The plasma insulin level exhibited a rapid increase at 30 minutes after the dosing of the insulin by the polyacrylic acid aqueous gel base. However, the plasma level quickly diminished in 1 hr. Contrary to our expectation, an addition of a non-ionic surfactant such as Tween 80 under pH 4--8 did not show further enhancement of the absorption. In an attempt to simulate a clinical condition in which insulin was given after a meal, the insulin gel was administered into the rectal loop in diabetic rats following the i.v. injection of glucose. A satisfactory result was obtained in which 5 IU/kg dose was able to suppress a rise in the blood glucose after the glucose loading.

The mechanisms of absorption enhancing effect by polyacrylic acid gel were investigated in rats. Polyacrylic acid gel significantly enhanced rectal absorption of phenol red, a hydrophilic compound. The enhanced absorption was concentration dependent in the range of 0.01-0.05% w/v polyacrylic acid in gel. The gel also significantly increased the influx and the net influx on water movement in rat rectum. Further, the histological change in rectal epithelium after administration of the polyacrylic acid gel was examined with transmission electron microscopy. The structural changes, which were removal of the mucus and fenestrations of the intercellular spaces 5 and 10 min after administration of polyacrylic acid gel, were observed. These changes were reversible and returned relatively soon to normal levels. Thus, the absorption promoting effect by polyacrylic acid gel may occur mainly with increased water influx as a driving force.

The rectal absorption of aminopyrine (AP) from a three-component-system suppository base (TCS), which is a mixture of oleaginous base, water-soluble base and the poly-(oxyethylene) poly-(oxypropylene) block copolymer, Unilube, was investigated. Albino rabbits were used as the animal model. The bioavailability of oleaginous base and water-soluble base (polyethylene glycol 4000) were 44.3% and 82.6%, respectively. The time to reach maximum plasma concentration (Tmax) of the oleaginous and the water-soluble bases were 21.0 +/- 8.2 min and 33.0 +/- 16.4 min, respectively. When TCS was used, its Tmax was 30 min and increasing the amount of Unilube in the base from 5% (w/w) to 20% (w/w) decreased the bioavailability from 100.4% to 47.2%. The softening temperature of TCS was 55-57 degrees C. Collectively, TCS containing 5% of Unilube gave significantly higher bioavailability than the other bases without softening until 57 degrees C. Also, the results of the two different release tests were compared with the results of an animal experiment in this paper.

Three kinds of suppositories were constructed with oleaginous base material (Witepsol H-15): a conventional type suppository containing propranolol (PPL) hydrochloride mixed with a base material (I), a hollow type suppository containing PPL in a form of aqueous solution (PPL was dissolved in isotonic NaCl solution) in its cavity (II), a hollow type suppository containing PPL as powder (hydrochloride salt) in its cavity (III). Bioavailability was estimated after rectal administration of each suppository in rabbits and compared with oral administration. The peak plasma PPL concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were lower with I than with II or III. The Cmax and the AUC measured after rectal administration of III were significantly higher than those in the case of oral administration. By using III, the highest values of the mean Cmax (795 +/- 160 ng/ml) and of the mean AUC (459 +/- 21 h X ng/ml) were obtained. It was found that systemic availability was increased by rectal administration of PPL hollow type suppositories. These data on bioavailability suggested that PPL was absorbed more efficiently with the hollow type suppository than with the conventional one. PPL was released faster from II and III than from I. It was concluded that the hollow type suppository was a suitable device for absorption of PPL into the rectum.

In order to estimate the application to rectum of calcium and magnesium salts of indomethacin (IND), the suppositories of the salts and IND were prepared using macrogol and Witepsol H-15 bases. The rectal administration of these suppositories (Witepsol H-15) was compared with the oral administration of IND and the salts. The hardness, melting point, and liquefaction time of the suppositories were similar between IND and the salts. The in vitro release of IND-Mg from the suppositories was significantly faster than that of IND, while the release of IND-Ca was slower. The area under the plasma drug concentration-time curve (AUC) after IND suppositories was significantly higher than that after oral administration of IND (p less than 0.01). The AUC value after IND-Ca suppositories was slightly higher than those after other suppositories, although the plasma levels in early period after IND-Ca suppositories were lower, indicating the slow absorption of IND-Ca. The multiple treatment with IND-Ca suppositories gave no histological change of the rectal mucosa. Therefore, the present results suggested that IND-Ca was favourable for the rectal administration, in high doses and repeatedly.

An in situ experimental model of rectal absorption was studied in rabbits compared with in vivo determination of drug concentration in the plasma of postcaval vein using indomethacin as drug. Pharmacokinetic parameters were similar between in vivo and in situ. When results from both studies were compared, 60% of the drug administered to the rectum was absorbed from the superior hemorrhoidal vein and the remaining 40% was absorbed from the inferior hemorrhoidal vein. When an aspirin suppository was used in this model, the amount of unaltered aspirin absorbed in the rectal mucosa or space was greater than the absorbed salicylic acid which was metabolized or degradated from aspirin. In the case of insulin, these differences were not seen in the insulin concentration of venous plasma between insulin physiological saline and surfactant suspension. However, using the in situ model, the surfactant effect on rectal absorption of insulin was observed. From the above results, it was concluded that this in situ experimental model of rectal absorption has advantages in that it can be used directly to measure the rectal absorption rate and to determine ratios of easily metabolized and poorly absorbed drugs. Therefore, this model appears to be useful in evaluation of rectal absorption.

The promoting effects of medium chain glyceride (MCG) on the rectal absorption of β-lactam antibiotics were compared among various experimental animals (such as rats, rabbits and dogs). The plasma levels of cefmetazole (CMZ) after rectal administration, when MCG was used as the vehicle, significantly increased in all animals, but the bioavailability of CMZ was greatly varied among the animal species ; the bioavailability of CMZ in dogs was apparently less than those in other animals (rats=rabbits > dogs). However, in dogs, the promoting effect of MCG on the rectal absorption of CMZ increased by addition of nonionic surfactants such as ether-type (Brij 30[○!R] and Brij 35[○!R]) and ester type (Nikkol MYL-10[○!R]). And the promoting effect of surfactants in the MCG vehicle is not always correlated with blood hemolysis, suggesting contribution of other physicochemical or biological factors.

The rectal absorption of pepleomycin sulfate (PEPS) in rats was increased significantly by the coadministration with each of diclofenac (DC), sodium 5-methoxysalicylate (5-MSA) and phenylalanine enamine of ethylacetoacetate (Enamine). 5-MSA increased the lymphatic uptake of PEPS after rectal administration while DC and Enamine did not. The mechanism behind the enhancing action of 5-MSA on the lymphatic uptake of PEPS may be due to the suppressing action of 5-MSA on the vascular permeability to PEPS. DC increased the vascular permeability to PEPS but Enamine did not affect it. Findings obtained in this study may indicate that adjuvant used acts independently at the rectal mucosal membrane and at the vascular membrane for membrane for membrane permeability to PEPS.

The mechanisms of the promoting effect of medium chain glyceride (MCG) containing glyceryl mono-, di- and tri-caprylate on rectal absorption of water soluble drugs were investigated. It was found that the solubility behavior of the drugs in mucosal fluids on the surface of the membrane are critical factor for the enhanced rectal absorption. Moreover, the drugs to be readily absorbed from MCG base may be ones of low partition coefficients to MCG phase as well as high solubility in water. And it was found that MCG can't be absorbed from the rectum, different from oral administration, suggesting an interaction of MCG with absorption membrane, rather than the carrier effect of MCG itself. Furthermore, from the results in the pretreatment experiments and additional administration of MCG alone, it was suggested that the interactions of MCG with the membrane components, as well as the induction of biological or physiological changes, may be at least partly responsible for the promoting effect of MCG.