5-[(2-Aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1 H-1, 2, 4-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a sleep inducer, is a ring-opened derivative of 1, 4-benzodiazepine and has been reported to be activated by intestinal aminopeptidases in a step of absorption. In this study, we investigated the role of the intestinal aminopeptidases in the uptake of 450191-S by the intestine by using various aminopeptidase inhibitors in everted sacs of rat small intestine in vitro. Glycylglycine did not affect the desglycylation of 450191-S but glycyl-L-leucine or L-leucyl-L-leucine inhibited the reaction. This inhibition was accompanied by reduced concentration of 450191-S metabolites in the intestinal tissue. When the incubation was carried out at 0°C or with puromycin, the desglycylation was also inhibited and the concentration was similarly reduced. Since the extent of inhibition of the desglycylation of 450191-S was negatively correlated with the total concentration of 450191-S metabolites in the intestinal tissue (r=-0.9660), the aminopeptidases must play an important role in the uptake of 450191-S by the intestine. To confirm this, we examined the uptake of the desglycylated product of 450191-S, 8-chloro-6-(2-chlorophenyl)-N, N-dimethyl-4H-1, 2, 4-triazolo-[1, 5-α] [1, 4]-benzodiazepine-2-carboxamide (M-1) in the same manner. No effect of dipeptides, puromycin or reduced temperature was found on M-1 uptake by the intestine, leading to the conclusion that the aminopeptidases are important for enhancing the uptake of 450191-S in the intestine.

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The in vivo percutaneous absorption and in vitro penetration of indomethacin (IND) and the calcium salt (IND-Ca) in ointments were investigated on rat abdominal skin under occlusions in the presence or absence of penetration enhancers. The absorption of IND-Ca from the gel (Hiviswako) ointment was significantly higher than that from a standard ointment of IND, an approximation of a commercial product. Sorbitan monooleate had no enhancer effect for the IND-Ca gel ointment, while the addition of calcium thioglycolate dramatically decreased the absorption of IND-Ca due to powdering of the ointment. The absorption of drugs was significantly increased by adding Azone^[○!R] in the gel ointment resulting in an approximate 3-fold increase in the parameters, C_max and AUC. The percutaneous absorption of drugs from white petrolatum base was relatively lower than that from gel ointment. The plasma IND concentrations after a topical application of the gel ointments for 6 h (3.0 cm×3.0 cm area, 1.0 g of 5% IND ointment) were over the therapeutically effective concentrations during 48 h. The bioavailability of IND after application of ointments was 9.1-27.8% for the gel base and 4.5-6.3% for the white petrolatum base. The in vitro penetration behavior of drugs using a Franz diffusion cell resembled the result of the in vivo absorption more closely. The relationship between the in vitro (the permeability coefficient and skin/ointment partition coefficient) and in vivo (C_max and AUC) penetration parameters was linear and there was a clear correlation between both parameters.

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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 (C_max) and the area under the plasma concentration-time curve (AUC) were lower with I than with II or III. The C_max 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 C_max (795±160 ng/ml) and of the mean AUC (459±21 h·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.

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The effect of medium chain glyceride (MGK^[○!R]) emulsion on the intestinal absorption and the biliary excretion of bromthymol blue (BTB) was investigated in rats. Extensive tissue accumulation of BTB was reduced when BTB was administered with MGK^[○!R]emulsion formulation. HCO-100, an emulsifier, was also important for the decrease in the tissue accumulation of BTB. The ratios of absorption percent to tissue accumulation percent and to free fraction, not contained in the droplet of emulsion, in MGK^[○!R]emulsion were much greater than that of the control. Pretreatment with BTB-free emulsion reduced BTB absorption under the control, although tissue accumulation was not affected. The absorption appeared to decrease with increase in the time of pretreatment. The effect of leaving treatment after pretreatment on the absorption of BTB was also investigated. With the increase in leaving time after pretreatment, reduced absorption tended to resume to the level of control. The change in monocaprylate content from 54 to 60% in MGK^[○!R]made a difference in BTB absorption and it was suggested that monocaprylate content in MGK^[○!R]was one of the significant factors of MGK^[○!R]emulsion on drug absorption. Bile recovery study was simultaneously carried out with an in situ recirculation experiment. The recovery of BTB into bile tended to decrease. The ratio of recovery percent of BTB into bile to the absorption percent of BTB also decreased extensively, which is possibly another effect of MGK^[○!R] on drug disposition.

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When murine lymphocytes were cultured in RPMI-1640 medium containing fetal calf serum (FCS) for more than 3 d without added antigens, suppressor T cells (Ts) that suppressed in vitro antibody responses to sheep erythrocytes, dinitrophenyl-Ficoll and trinitrophenyl (TNP)-lipopolysaccharide nonspecifically were induced spontaneously. Thus, we failed to detect the activities of antigen-specific Ts that are generated by priming the lymphocytes in vitro with a specific antigen under these experimental conditions. To avoid the induction of nonspecific Ts, we examined various culture conditions and found that nonspecific Ts were not induced only when a specific lot of FCS (NSF 107) was used. When the lymphocytes were cultured with Keyhole limpet hemocyanin (KLH) in NSF 107-containing culture medium, we could detect KLH-specific Ts activity that specifically suppressed the secondary response to TNP-KLH without the interference of nonspecific Ts. Similar experiments were successful if were used FCS that was previously treated at 70°C for 10 min instead of native ones. Immunoelectrophoretic analysis revealed that the level of a component belonging to α-globulin fraction was markedly low in NSF 107 as compared with all other lots of FCS that could induce nonspecific Ts. Removal of this component from FCS by an immunoadsorbent resulted in the loss of the capacity to induce nonspecific Ts. On the other hand, when the lymphocytes were cultured in the presence of varying amounts of this component, nonspecific Ts were generated in a dose-dependent manner.

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In order to study whether a part of the antihypertensive action of orally administered diltiazem is mediated by the central nervous system and whether metabolites of diltiazem contribute to the actions of diltiazem, we compared the effects of diltiazem and its main metabolites on blood pressure by intravenous administration with those by intracere-broventricular administration to spontaneously hypertensive rats (SHR). Contents of diltiazem and its metabolites in the brain of SHR after oral administration were also studied. Hypotensive action of intravenously administered diltiazem was stronger than that of its main metabolites in terms of potency and durability. Diltiazem (30 μg or more) and its main metabolites (100 μg) showed weak hypotensive action by intracerebroventricular administration. Oral administration of diltiazem (30 mg/kg) decreased mean blood pressure by about 40 mmHg 30 min after the administration. At this time, contents of unchanged form and metabolites of diltiazem in the brain were 0.78±0.10 and 7.58±0.89 μg/whole brain, respectively. It was suggested that hypotensive action of diltiazem was mainly attributable to the unchanged form and that the contribution of central action to the acute hypotensive action of diltiazem was unlikely, although centrally administered diltiazem can cause systemic hypotension.

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The hypotensive action of diltiazem by oral administration to conscious renal hypertensive dogs (one kidney, one figure 8) was studied and the effect was compared with that of nifedipine. Diltiazem decreased mean blood pressure 10-20 mmHg at doses of 1-4 mg/kg. The same doses of nifedipine exhibited hypotensive actions similar to diltiazem, but nifedipine induced a more pronounced reflex tachycardia than diltiazem. Combined administration of diltiazem with pindolol produced a greater hypotension than that caused by individual drugs and caused an increase in heart rate, smaller than by pindolol alone and larger than by diltiazem alone. When 60 mg of diltiazem was administered 3 times a day for 10 consecutive days, blood pressure decreased 15 mmHg on the third day or later. Although the time course of plasma level of diltiazem on the last day was similar to that on the first day, the heart rate initially increased slightly and decreased later. Prolongation of the PQ interval of an electrocardiogram was diminished after the fourth day. In conclusion, diltiazem decreased blood pressure of renal hypertensive dogs at doses comparable to those used for clinical treatment in acute and chronic experiments.

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