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Trandolapril is the prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It has been proposed that its active metabolite, trandolaprilat, is mainly excreted in bile, but this has not been clearly demonstrated. Recently it has been reported that temocaprilat, an active metabolite of the ACE inhibitor temocapril, is effectively excreted in bile via an ATP-dependent active transporter (canalicular multispecific organic anion transporter: cMOAT). To investigate whether trandolaprilat has the pharmacological ability to affect the cMOAT system in a manner similar to temocaprilat. The lipophilicity of trandolaprilat and temocaprilat was measured to determine the n-octanol-water partition coefficients. The dose-dependent inhibition of the uptake of [3H]-estradiol-17β-D-glucuronide and [3H]-2, 4-dinitrophenyl-S-glutathione, which are good substrates for cMOAT, in canalicular membrane vesicles (CMVs) prepared from Sprague-Dawley rats was determined in the presence of trandolaprilat and temocaprilat. The partition coefficient of trandolaprilat (log Po/w−1.1) was about 30 times higher than that of temocaprilat (log Po/w−2.5). The uptake of [3H]-estradiol-17β-D-glucuronide and [3H]-2, 4-dinitrophenyl-S-glutathione was dose-dependently inhibited by the presence of temocaprilat, but trandolaprilat had no effect on the transport of [3H]-estradiol-17β-D-glucuronide or [3H]-2, 4-dinitrophenyl-S-glutathione into CMVs even at concentrations as high as 200μM. It could be concluded that trandolaprilat has a higher lipophilicity than temocaprilat. But the hepatobiliary excretion system via cMOAT may not contribute to the excretion of trandolaprilat in bile. (Hypertens Res 2001; 24: 235-240)

Sites of the muscle relaxant action of CS-722 were investigated in rats. Doses injected intra-4th ventricularly (i.c.v.) or intrathecally (i.t.) were determined according to measurements of CS-722 concentration in the brain stem and the spinal cord after systemic administration. When administered i.c.v. (50 and 100 micrograms) or i.t. (200 and 400 micrograms), CS-722 reduced the radio frequency decerebrate rigidity, although the effect after i.c.v. injection was transient. These results indicate that CS-722 exerts its muscle relaxant action by affecting both the supraspinal structure and the spinal cord. Spinal reflexes were not affected by CS-722 injected i.c.v. It seems that muscle relaxation is not always accompanied by impairment of the spinal reflex.

The glucuronide of a new oral antidiabetic agent, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl- methoxy)benzyl]thiazolidine-2,4-dione (CS-045) (1), was synthesized to confirm the structure of a metabolite in monkeys (Macaca fascicularis) and to examine its antidiabetic activity. The glucuronide also had antidiabetic activity in KK-mice.

The degradation kinetics of pivaloyloxymethyl (POM) esters of cephalosporins in phosphate buffer solution (pH 6-8) were investigated. The degradation of the starting delta 3 cephalosporin ester proceeded mainly via isomerization to the delta 2 ester and subsequent hydrolysis to the delta 2 acid. Hydrolysis to the delta 3 acid (the parent acid) was very slow. Analysis of the rate constants indicated that the isomerization rate k12 was approximately equal to the apparent degradation rate of the delta 3 ester kdeg, and slower than the hydrolysis rate of the delta 2 ester k24. The isomerization process to the delta 2 ester was found to be the rate-determining step in the degradation of cephalosporin esters. The substituent at the C-3 position of the cephalosporins affected the degradation kinetics. The degradation was accelerated by increase of pH, buffer concentration and added protein.

Oral acute toxicity of medium chain glyceride (MCG) was studied in mice and rats. In mice and rats, clinical signs such as irregular respiration, laxity of movement, staggering gait and loss of righting reflex appeared after single oral administration of MCG at a relatively large dose. The LD50 values determined in male and female mice were 26.9 and 28.5 ml/kg, and in male and female rats were 27.4 and 26.7 ml/kg, respectively. In order to evaluate the biological safety of MCG suppository of cefmetazole sodium (CMZ), its local irritation on the mucous membrane was studied. Primary eye irritation of MCG suppository of CMZ was studied in rabbits. Although mild irritation was seen in conjunctivae, no remarkable changes were observed in cornea and iris. Furthermore, primary effect of MCG suppository of CMZ on the rectal mucous membrane was studied macro- and micro-scopically. It was observed that remarkable histological changes of rectal mucous membrane by MCG suppository of CMZ were not observed in all animals used.

The distribution of orally and intravenously administered 14C-oxazolam was studied in mice by means of whole-body autoradiography and in rats by scintillation counting of the organs and tissues. The radioactivity was found to be widely distributed in various tissues including the brain at 30 min after oral administration, reached the maximum levels within 1 hr and thereafter declined rather rapidly. The distribution patterns were similar for mice and rats, except that the brain uptake of the drug was appreciably higher in mice than in rats. A high affinity of oxazolam to the brain tissue was demonstrated by an extremely high and rapid uptake of radioactivity by the brain after intravenous injection in mice. The brain level reached its maximum at about 1 min after the injection and thereafter fell off rapidly, some retention of radioactivity being observed in the white matter of the brain-stem and in the trigeminal nerve. Autoradiographic studies in pregnant mice demonstrated that there is a slow and only a slight penetration of radioactivity through the placenta. A comparison of the excretion patterns of oxazolam after oral administration in mice, rats, dogs and man revealed that in mice and rats the excretion in the feces, mostly derived from the biliary excretion, was more important than that in the urine, while in dogs a larger part was excreted in the urine and in man the most part (ca. 80% of the dose) in the urine.

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 effect of medium chain glyceride (MCG) on the intestinal absorption of cefmetazole sodium (CMZ) was investigated in rats and dogs. In rats, MCG containing glyceryl mono-, di- and tri-caprylate enhanced the intestinal absorption of CMZ after intraduodenal administration, though the promoting effect of MCG was less than that after rectal administration. The promoting effect of MCG was found to be mainly due to glycerylmonocaprylate and dependent on the dosage of MCG. The plasma CMZ levels after intraduodenal administration as MCG solution tended to be slightly higher than those observed after administration as MCG emulsion, though the differences were found to be statistically insignificant. Moreover, the intestinal absorption of CMZ after intraduodenal administration as MCG emulsion was decreased significantly by increasing the amount of water in the emulsion. The promoting effect of MCG in dogs was more clearly demonstrated in the lower intestine than in the upper intestine. Furthermore, the oral bioavailability of pharmaceutical formulations of CMZ was also investigated in dogs. When enteric coated capsules filled with MCG solution were administered to dogs, the bioavailability of CMZ was enhanced significantly.

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.

The effect of medium chain glyceride on the rectal absorption of cefmetazole sodium is investigated using an in situ experiment in rats. Each glyceride component of medium chain glyceride was separated using a high-performance liquid chromatographic method. The promoting effect of medium chain glyceride was found to be mainly due to glycerylmonocaprylate and dependent on the concentration of glycerylmonocaprylate. When cefmetazole sodium in medium chain glyceride solution was administered into the rectal lumen of rats, rapid absorption of the drug was observed leading to a residual amount of about 45% at 15 min after administration. The promoting effect of medium chain glyceride was found to be more effective in the rectum than in the small intestine.