6-Amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate (FUT-187), a novel protease inhibitor, is an ester of 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoic acid (IABA) and 6-amidino-2-naphthol (AN). Absorption, distribution and excretion of FUT-187 were investigated in rats after single oral (1. 10. 30 and 100mg/kg) or intravenous (1 mg/kg) administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187.
1. Blood levels of radioactivity (¹⁴C) after oral administration were higher in case of [¹⁴C-AN] FUT-187 administration, however, after intravenous administration, higher blood levels were observed in case of [¹⁴C-IABA] FUT-187. It was suggested, from the viewpoint of the different profiles of blood levels of ¹⁴C, that FUT-187 was easily hydrolized to its constituents by calboxvl-esterases.
2. Tissue distribution pattern of ¹⁴C was similar to the blood levels profiles. High levels of ¹⁴C were observed in the liver and kidney after oral administration of both forms of labeled FUT-187, but there was no evidence of accumulation of ¹⁴C in any tissues.
3. In general, urinary excretion of ¹⁴C after oral administration was higher in case of[¹⁴C-AN] FUT-187 administration, but the excretion ratio was not proportional to administered dose.
4. The levels of ¹⁴C in the milk and fetuses were lower than those in the meternal blood.
5. Binding of ¹⁴C to human, dog or rat serum albumins was about 10.2 ?? 35.2%.

View full abstract

6-Amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate (FUT-187), a novel protease inhibitor, is a ester of 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino] benzoic acid (IABA) and 6-amidino-2-naphthol (AN). Blood concentration, distribution, excretion and accumulation of FUT-187 were investigated in male rats after consecutive oral administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 for 7 or 21 days.
1. During the consecutive oral administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 for 21 days, the blood radioactivity was constant at 1hr for [¹⁴C-IABA] FUT-187, at 3hr for [¹⁴C-AN] FUT-187 and at 24hr for both labelled forms of FUT-187 after each dosing.
After the consecutive oral administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 for 21days, blood level profiles were similar to those after a single administration.
2. After the consecutive oral administration of FUT-187, labelled at either position, for 21days, the total radioactivity in almost all organs decreased rapidly with similar patterns those observed after a single administration.
There was no clear indication of accumulation of FUT-187.
3. The excretion of radioactivity in the urine and feces was constant during consecutive oral administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 for 7days.
Within 8 days after the last dosing of [¹⁴C-IABA] FUT-187, 6.0% and 92.0% of administered radinactivity was excreted into the urine and feces. respectively.
In case of [¹⁴C-AN]FUT-187, 40.9% and 52.7% of the administered radioactivity excreted into the urine and feces, respectively.

View full abstract

6-Amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate (FUT-187), a novel protease inhibitor, is a ester of 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoic acid (IABA) and 6-amidino-2-naphthol (AN).
During the course of the studies on the physiological disposition of FUT-187 in rats, the tissue distribution of radioactivity in albino male, pregnant and pigmented male rats after a single oral administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 (30mg/kg) was investigated by wholebody autoradiographv (WARG).
1. In both cases of administration of[¹⁴C-IABA]FUT-187 and [¹⁴C-AN] FUT-187, WARG showed high levels of radioactivity in the kidney, liver, skin, epididymis, submaxillary gland, aorta and esophagus. WARG at 24hr after oral administration of FUT-187 labelled at either position showed that radioactivity remained only in the intestinal contents and urine present in the bladder.
2. In female rats on day 13 and 19 of gestation, much lower levels of radioactivity were observed, indicating a difficult passage through the placenta into the fetuses after oral administration of FUT-187 labelled at either position.
3. WARG of pigmented male rats after oral administration of FUT-187 labelled at either position showed that the radioactivity was not specifically distributed to any tissues.

View full abstract

6-Amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate (FUT-187), a novel protease inhibitor, is a ester of 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoic acid (IABA) and 6-amidino-2-naphthol (AN). The metabolism of FUT-187 was studied after a single oral administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 to male rats at a dose of 30mg/kg.
1. Major metabolite of FUT-187 after oral administration of [¹⁴C-IABA] FUT-187 was IABA Dresent in the urine. feces and bile.
Only a small quantitiies of the unchanged FUT-187 were found in excreta. Minor metabolites, i.e., IABA glucuronide was found in urine.
2. Major metabolite of FUT-187 after oral administration of [¹⁴C-AN] FUT-187 were found to be AN-glucuronide and AN in the urine, feaces, bile, blood, liver, kidney and pancreas.
3. The concentrations of unchanged FUT-187, which is strongly related to its efficacy were 10 ?? 111 times higher in the liver, kidney, lung and pancreas than those in the blood.

View full abstract

6-Amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate (FUT-187), a novel protease inhibitor, is a ester of 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoic acid (IABA) and 6-amidino-2-naphthol (AN).
The absorption, distribution, metabolism, excretion and protein binding of ¹⁴C-labelled FUT-187 were studied in male beagle dogs after oral or intravenous administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 at 1, 15 or 30mg/ke.
1. [¹⁴C-IABA] FUT-187 and [¹⁴C-AN] FUT-187, administered orally to dogs at 15mg/kg, gave their maximum concentration in blood of ca. 889 and 601 ng eq. /ml, the area under the curve ( 0 ?? 48hr) of ca. 9163 and 11293 ng eq. •hr/ml, elimination half-life of ca. 11 and 12hr. respectively.
2. The maximum concentration(C_max) of unchanged drug in the plasma after oral administration of [¹⁴C-AN] FUT-187 at a dose of 30mg/kg to dogs was ca. 406ng/ml.
Compared with rats (ca. 30ng/ml), animal difference was observed of the C_max in the Dlasma.
3. After oral administration of [¹⁴C-IABA] FUT-187 (15mg/kg), the concentration of unchanged drug in pancreas was ca. 4 times that in the plasma. In other tissues, the concentration of unchanged drug were also higher than in the plasma, indicating that FUT-187 had a high affinity for tissues.
The liver concentration of unchanged drug in the dogs was higher than in the rats.
4. FUT-187 was subjected to the first-pass effect and was hydrolyzed to IABA and AN moieties, followed by conjugation of an AN moiety by small intestine and or liver.
5. The percent binding of ¹⁴C-FUT-187 to the dog serum protein in vivo was ca. 51 ?? 65%.
6. Little FUT-187 was found in the brains.
7. After oral administration of [¹⁴C-IABA] FUT-187 or [¹⁴C-AN] FUT-187 (15mg/kg), dogs excreted ca. 23 or 39% of the radioactivity in the urine, and ca. 73 or 55% in the feces, respectively.

View full abstract

Sulfonylureas are the hypoglycemic agents that have been used to treat non-insulin dependent diabetes mellitus patients for decades. Commonly used doses differ to a high extent among sulfonylureas.
Recent studies have shown the presence of a receptor on the plasma membrane of the β-cell specifically binding all these drugs. The binding affinity constant (Kd) of sulfonylureas to its receptor correlates well with their potencies of the induction of insulin secretion. In this study, we investigated the relationship between Kd value and plasma unbound drug concentrations (C_f) after administration of the usual doses of several sulfonylureas in human and obtained a good positive correlation between these two parameters, Kd and C_f.
The calculated receptor occupancy (∅=C_f/(Kd+C_f)×100%) of these drugs showed a constant value (56.7±10.8%) regardless of a wide range of administered doses. It was successful to predict both the therapeutic blood concentrations and usual doses of sulfonylureas, based on the good correlation between Kd value and plasma unbound concentration.

View full abstract

Two novel metabolites of felodipine were isolated from rat bile or in an in vitro system using rat liver preparations. Their chemical structures were identified by comparative analysis with authentic samples.
Both metabolites were formed by ester hydrolysis of felodipine. One was a 3-carboxyl derivative and the other a 5-carboxyl derivative ; both were identified as having dihydropyridine structures and were shown to be major metabolites in rat plasma.

View full abstract

¹⁴C-Nifedipine suppository was administered intrarectally (i.r.) in rat, in order to investigate its absorption, distribution, metabolism and excretion, comparing with the data after intravenous (i.v.) or oral (p.o.) administration of ¹⁴C nifedipine solution. Also the metabolic fate was investigated after daily dosing of ¹⁴C-nifedipine suppository.
1. After i.v. administration, the level of radioactivity in the blood decreased biphasically, with the corresponding half-lives of 1. Ohr and 38.5hr, respectively. The maximum concentration of radioactivity in the blood at 45min after i.r. administration was higher than that observed after p.o. application.
2. The excretion ratio of radioactivity in the urine and feces was similar among those 96hr after i.r., i.v. and p. o. administration ; 51 ?? 53 and 46 ?? 41% of dose in the urine and feces, respectively.
3. The distrubution of radioactivity in tissues after i.r. administration was similar to that of p.o. administration except that in gastro-intestinal tract. At 45min after i.r. administration, the tissue levels of radioactivity were higher in the liver, kidney and plasma than blood, and very low in brain.
4. Metabolites in the plasma and urine after 3 different administration routes were simil ar. Unchanged ¹⁴C-Nifedipine was found in plasma at the early period after administration, but not in urine.
5. During the repeated intrarectal administration, the level of radioactivity in the blood at 24hr after daily dosing continued to increase till the 7th day, then reached to the plateau.
The excretion rates of radioactivity in the urine and feces were nearly constant during the period of repeats, and were similar to those after a single administration. The tissue levels of radioactivity appeared not to be accumulated in the tissues.

View full abstract

Distribution of radioactivity into the brain and spinal cord was studied after oral administration of ¹⁴C-HY-770 in rats. The radioactivity was measured by the quantitative analysis of autoradiogram. The autoradiogram was recorded by video camera system and then analyzed with computer-assisted image analyzer.
1. The distribution of radioactivity in each region of the brain was uniform at any measurment points.
2. The concentration in the spinal gray matter was nearly equal to the regions in the brain, but the concentration in the spinal white matter was slightly lower than that in other regions.
3. The all regions in the brain and spinal cord showed higher concentration than in the blood. The differences of the partition ratios (each region/ blood) depending on a measurement time were not observed.

View full abstract

Glutathione conjugation, which has long been considered as a major detoxication pathway, leads to the formation of toxic metabolites in certain kinds of xenobiotics. Sulfur-containing conjugates are classified into three types on the basis of mechanism of toxication : Type I ) conjugates that exert toxicity without bioactivation (direct-acting conjugates), Type II) conjugates that require metabolic activation, and Type III) conjugates that are transported to the target cell and exert their toxicity upon deconjugation. This review summarizes the current knowledge on the vast metabolic pathway of cysteine conjugates and the mechanism of toxication of the conjugates classified into the type II. Metabolic pathway of cysteine conjugates includes : 1) N-acetylation, 2) C-S cleavage, 3) deamination, 4) S-oxidation, and 5) decarboxylation. Among these, the involvement of C-S cleavage pathway in the toxication of cysteine conjugates is well established. Cysteine conjugates of some halogenated alkenes that are categorized to the type II are converted to chemically reactive thiols by the action of cysteine conjugate β-lyase. The penultimate toxic intermediates, thiols, are further converted to highly electrophilic thionoacyl halides or thioketenes which covalently bind to nucleophilic site of cellular macromolecules. In addition, we discuss possible contribution of other metabolic pathways to the toxication of cysteine conjugates.

View full abstract