In order to classify opioid agonists and antagonists based on the receptor occupancy in the brain, the information on the therapeutic plasma concentration of these drugs and the binding affinity to μ opioid receptor was collected. The analysis was performed on eight opioid agonists (morphine, sufentanil, fentanyl, methadone, pethidine, levorphanol, buprenorphine and pentazocine) and two antagonists (naltrexon and naloxon) obtained data on the plasma concentration after therapeutic dosing, the plasma unbound fraction and dissociation constant (K_d) of the brain receptor binding. The mean plasma concentration and unbound plasma concentration varied 4000 and 10000 fold among the opioid agonists, respectively. Moreover, no difference in the plasma concentration or unbound plasma concentration was observed between the agonists and antagonists. On the other hand, the binding occupancy of the agonists to receptor (ranged 1.4-25.0%) calculated using the value of K_d with addition of sodium ions and therapeutic concentration of unbound drug was substantially smaller than that of the agonists (57.1-96.0%), although no difference in the binding occupancy calculated using the K_d without addition of sodium ions was observed between the agonists (ranged 1.8-89.0%) and antagonists (57.1-96.0%). From these results, the receptor occupancy of opioid calculated using the value of K_d with addition of sodium ions may be more useful index for the classification of opioid agonists and antagonists.

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Flumazenil (FMZ), a benzodiazepine receptor antagonist, is used to reverse the central effects of benzodiazepines (ex. sedation or intoxication with over dose). It inhibits the effects of benzodiazepine receptor agonists by competing with these drugs. The purpose of this study was to calculate the benzodiazepine receptor occupancy of FMZ using the pharmacokinetic parameters reported in the literature, and to examine the relationship between the receptor occupancy and the pharmacological effect of FMZ. Recovery of consciousness in the patients sedated with intravenous flunitrazepam was used to indicate the pharmacological effect of FMZ.
In contrast with the plasma concentration of FMZ which declines rapidly after intravenous administration, the effect (recovery of consciousness) appeared relatively slowly in about 5 to 10 minutes. Therefore, there was no correlation between plasma concentration and the effect of FMZ. On the other hand, the receptor occupancy of FMZ, calculated considering the association/dissociation process at the receptor, correlated well with the effect, giving the similar pattern for various doses of FMZ. These findings indicate that the receptor occupancy is a suitable indicator of the pharmacological effects of benzodiazepine antagonists and that receptor occupancy by antagonist of more than 30% was required for all the patients to become conscious with FMZ.

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The uptake mechanism of tetramethylammonium (TMA) and tetraethylammonium (TEA) ions was investigated using the isolated rat hepatocytes. TMA and TEA were trans ported against concentration gradient into the isolated hepatocytes. The cellular uptake of TMA and TEA was inhibited by their structural analogs and metabolic inhibitors, and was also temperature-dependent. The uptake of these compounds showed saturation with in creasing extracellular concentration. Thiamine, the endogenous quaternary ammonium, and hemicholinium-3 markedly inhibited the cellular uptake of TMA and TEA. The inhibition by choline was moderate. The mode of uptake inhibition by thiamine and choline was the competitive type of inhibition. These results suggested that TMA and TEA are trans ported into the hepatocytes by the common carrier system same as most likely that for thiamine.

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The entero-hepatic circulation of 9-amino-8-fluoro-1, 2, 3, 4-tetrahydro-2, 4-methanoacridine citrate (SM-10888) in rats was investigated after oral administration and/or duodenal infusion of a pooled bile sample.
1. Pooled bile obtained from a rat receiving an oral dose of ¹⁴C-SM-10888 (5 mg/kg) was infused into the duodenum of bile-duct cannulated rats. At 72 hr after starting infusion, percentage values for infused radioactivity excreted into the urine (23%) and bile (41%) indicated that at least 64% of the radioactivity in the bile was reabsorbed.
2. Infused bile contained the N-glucuronide of SM-10888 (SMG, 15%) and the O-glucuronide of the hydroxylated metabolite M₃ (M₃G, 42%). In the urine and bile from rats receiving infusion of the pooled bile sample, the M₃G was the major component.
3. After oral administration of ¹⁴C-SM-10888, M₃G level in the urine from non-operated rats (24% of dose) was greater than from bile-duct cannulated rats (10% of dose), reflecting reabsorption of metabolites in the bile and excretion as M₃G.
4. SMG and M₃G, present in the infused bile sample, liberated unconjugated SM-10888 and M₃ after incubation with intestinal contents. Therefore it was assumed that the enterohepatic circulation included hydrolysis of SMG and M₃G in the bile to SM-10888 and M₃ by intestinal flora, reabsorption from gastrointestinal tract and subsequent further metabolism to M₃G.

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The pharmacokinetics of E3810 was investigated in rats and dogs. E3810 and its metabolites in plasma were measured by HPLC.
After a single intraduodenal administration of E3810 (5, 20 and 80 mg/kg) to male rats, the drug was absorbed rapidly and showed t_max at 5 minutes. The elimination half life of E3810 in plasma ranged from 6 to 8 minutes. The relation ship between dose and AUC was not linear, and the mean bioavailability was 36.6% after administration of 20 mg/kg. Following a single intraduodenal administration (20 mg/kg) to female rats, the mean bioavailability was 90.7% and higher than that of males.
When male and female rats were orally given 2-20 mg/kg of E3810, the bioavailabilities were 4.1-21.1% without sex difference. The AUCs after oral doses in males and females were smaller than those after intraduodenal doses, because of unstability of E3810 under acidic conditions such as those present in the gastric juice.
After a single oral administration of doses of 0.5, 1.5 and 5 mg/kg to the fasted dogs, being given oral dosing of 1% sodium bicarbonate solution before and after the administration of E3810, the plasma levels reached a peak at 8-12 minutes after dosing. The elimination half lives were 21-26 minutes. The relationship between dose and AUC was approximately linear and the bioavailability at a dose of 1.5 mg/kg was 81.4%. When the secretion of gastric juice was stimulated by pentagastrin given intramusculory, the plasma level of E3810 was markedly lower than that in untreated dogs.

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The absorption, distribution, metabolism and excretion of E3810 were studied in rats after administration of [benzimidazole-2-¹⁴C] E3810 (abbreviated as ¹⁴C-E3810) or [alpha methylene-¹⁴C] E3810.
After a single intraduodenal dose of ¹⁴C-E3810 (20 mg/kg) to rats, the blood level of radioactivity reached maximum at 15 minutes (3.86μg eq./ml of blood) and then was eliminated extremely slowly.
In rats, the radioactivities in blood cells and thyroid tissue remained for a long time following administration of ¹⁴C-E3810. On the other hand, radioactivities in these tissues after dosing of [alpha methylene-¹⁴C] E3810 were eliminated faster than after dosing of ¹⁴C-E3810. Therefore, the long half life time in blood cells and thyroid tissues after dosing of ¹⁴C-E3810 should be attributed to the moiety of benzimidazole ring labeled with ¹⁴C.
After addition of ¹⁴C-E3810 to blood in vitro, the incorporation of ¹⁴C to blood cells in rats was higher than these in dogs and in humans.
After intraduodenal administration of ¹⁴C-E3810, the radioactivity rapidly distributed to the tissues except for the thyroid and the distribution of radioactivity into the brain was very low. The radioactivity in the tissues were rapidly eliminated, except the blood cells and the thyroid. Distribution of radioactivity to gastric mucosa, the target tissue, after intravenous dose was shown clearly by the whole body autoradiography.
The main metabolites in plasma were UM-1, and UM-2, with small amounts of unchanged compound, M-1, and M-2 at 15 minutes after dosing of ¹⁴C-E3810. In the hepatic portal vein, over 70% of the radioactivity was recovered as unchanged compound after intraduodenal dose in situ experiment, therefore it was suggested that E3810 is mainly metabolized in liver.
The urinary and fecal excretions of radioactivity were 39.75% and 56.32% of dose, respectively for 8 days after intraduodenal administration of ¹⁴C-E3810 to rats. The biliary excretion of radioactivity was 60.86% of dose 24 hours after intraduodenal administration in bile duct-cannulated rats.

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The absorption, distribution, metabolism and excretion of the main metabolites, 1-ethoxymethyl-5-fluorouracil (EM-FU, a masked form of 5-fluorouracil), 3-cyano-2, 6-dihydroxypyridine (CNDP, a potent inhibitor of dihydrouracil dehydrogenase) and 5-fluorouracil (5-FU), after a single and repeated oral administration of BOF-A2 (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl]-1-ethoxymethyl-5-fluorouracil) were investigated in rats.
1. There was no difference in the plasma concentration profile of each metabolite between SD and Donryu rats.
2. Cmax and AUC_0-24hr of each metabolite increased in dose-dependent manner, but showed non-linearity at the dose of 1000 mg/kg.
3. The plasma concentration of 5-FU was observed for a longer period after administration of BOF-A₂ than after co-administration of 5-FU and CNDP or of EM-FU and CNDP.
4. After a single administration to fasting and non-fasting male rats, the plasma concentration of EM-FU was higher in non-fasting rats and those of CNDP and 5-FU were higher in fasting rats.
5. After a single administration to male and female rats, the plasma concentration of EM-FU was higher in females, while that of 5-FU was higher in male rats.
6. The serum concentration of 5-FU in tumor-bearing male rats was lower than the plasma concentration in normal male rats. It was considered that these differences in the plasma concentrations of EM-FU and 5-FU are mainly dependent on the activities of EM-FU metabolyzing enzyme and that the difference in CNDP concentration was due to a different absorption.
7. After a repeated administration to male rats, the plasma concentration of EM-FU was higher and that of 5-FU was lower on Day 7 than on Day 1.
8. At 2-8 hr after a single administration to male and female rats, the concentrations of EM-FU, CNDP and 5-FU were higher in the digestive organs and kidney than in the plasma, but declined rapidly until 24 hr after the administration. In male rats, none of the metabolites showed any accumulation in tissues after a repeated administration.
9. After a single concurrent administration of cimetidine or cisplatin with BOF-A2 to male rats, the plasma concentration and urinary excretion of EM-FU increased and those of 5-FU decreased compared to the BOF-A2 administration alone. This result suggested that cimetidine and cisplatin inhibited the activity of EM-FU metabolizing enzyme.
10. Within 48 hr after a single administration to male rats, the urinary excretion of the metabolites was 6.8% for EM-FU, 17.9% for 5-FU and 58.4% for CNDP. 6.6% of BOF-A2 was detected in feces. Bilary excretion of each metabolite was very low.
11. After a repeated administration to male rats, the urinary excretion of EM-FU increased and that of 5-FU decreased.
12. After a repeated administration at 3, 10, or 30 mg/kg/day for 14 days to male rats, NADPH Cytochrome C reductase activity decreased in dose-dependent fashon, with DHUDase activity increasing at 30 mg/kg/day.

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The absorption and excretion of the main metabolites, 1-ethoxymethyl-5fluorouracil (EM-FU, a masked form of 5-fluorouracil), 3-cyano-2, 6-dihydroxypyridine (CNDP, a potent inhibitor of dihydrouracil dehydrogenase) and 5-fluorouracil (5-FU), after a single and repeated oral administration of BOF-A2 (3-[3 (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl]-1-ethoxymethyl-5-fluorouracil) were investigated in dogs, monkeys and guinea pigs. The plasma profiles of benzoic acid and isophthalic acid were also studied.
1. After a single administration to fasting and non-fasting dogs, EM-FU reached C_max at 8 hr and declined with the biological half life (T_1/2) of 19.4 and 48.2 hr, respectively. There were no differences in the plasma concentrations of EM-FU and CNDP between fasting and non-fasting dogs. 5-FU was not detected in the plasma at any time studied.
2. After a single administration to dogs, isophthalic acid was detected in the plasma but showed a lower concentration than EM-FU and CNDP.
3. After a repeated administration to monkeys at 6 or 20 mg/kg/day, EMFU, CNDP and 5-FU showed dose-dependent plasma concentrations on Day 1. Each metabolite was gradually eliminated from the plasma. At 20 mg/kg, EMFU and CNDP declined with a T_1/2 of 22 and 10 hr, respectively, and the concentration of 5-FU continued to increase until 24 hr after administration.
4. After a repeated administration to monkeys, the Cmax and AUC_0-24 hr, of 5-FU tended to decrease as the dosing periods were prolonged, and T_1/2 was shortened.
5. After a single administration to monkeys, no benzoic acid was detected in the plasma at any time studied. Isophthalic acid showed C_max at 1 hr, but was eliminated slowly after 6 hr.
6. After a single administration to guinea pigs, neither 5-FU nor benzoic acid were detected in the plasma at any time studied.
7. Within 72 hr after a single administration to dogs, urinary excretion of the metabolites was 10.1% for EM-FU and 30.1% for CNDP, with almost no 5-FU being excreted in the urine. Within 96 hr after single administration to monkeys, urinary excretion of the metabolites was 12.7% for EM-FU, 7.1% for 5-FU and 50.9% for CNDP. The excretion of each metabolite in dogs and monkeys tended to be delayed as compared to that in rats.

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The absorption, distribution, metabolism and excretion of radioactivity and the main metabolites, 1-ethoxymethyl-5-fluorouracil (EM-FU, a masked form of 5-fluorouracil), 3-cyano-2, 6-dihydroxypyridine (CNDP, a potent inhibitor of dihydrouracil dehydrogenase) and 5-fluorouracil (5-FU), after a single and repeated oral administration of ¹⁴C-BOF-A2 (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl]-1-ethoxymethyl-5-fluorouracil) were investigated in rats.
1. After a single administration to fasting and non-fasting male rats, blood levels of the radioactivity were higher in fasting than in non-fasting rats.
2. After a single administration to male and female rats, there was no marked difference in blood levels of the radioactivity between male and female rats.
3. After a repeated administration to male rats, the C_max of blood radioactivity on Day 7 and 14 increased 1.8 and 2.2 times respectively, as compared to values on Day 1. The AUCO-24 hr increased in a manner similar to the C_max.
4. After a single administration to male and female rats, the ratio of the AUC_0-24 hr of 5-FU to total radioactivity was 7% in male and 5% in female, and that of EM-FU to total radioactivity was 63% in male and 78% in female.
5. After a single administration to male and female rats, the level of the radioactivity was higher in the liver, kidney, adrenal and bone marrow than in the plasma between 2-8 hr except for the stomach and small intestine. After 12 hr, elimination of the radioactivity from many tissues was slow compared to that from the plasma, and the radioactivity tended to remain.
6. After a repeated administration to male rats for 14 days, elimination of the radioactivity 24 hr after the final dosing was slow and the radioactivity tended to remain in many tissues.
7. Within 7 days after a single administration to non-fasting male rats, the excretion of the radioactivity accounted for 47.1% in the urine, 41.1% in the feces and 8.6% in the expired air. 1.2% remained in the body. The excretion was almost completed within 48 hr. Within 48 hr after a single administration to fasting male rats, the excretion of the radioactivity accounted for 64.9, 13.1 and 11.8% in urine, feces and expired air, respectively.
8. After a repeated administration to male rats for 14 days, the excretion of the radioactivity within 24 hr after each dose accounted for 40% in the urine, 35-55% in the feces and 10% in the expired air, showing no notable changes due to repeated administration.
9. Within 24 hr after a single administration to fasting and non-fasting male rats, the ratio of EM-FU to total radioactivity excreted in the urine amounted to 13% in fasting rats and 56% in non-fasting rats, and that of 5-FU amounted to 24% in fasting rats and 9% in non-fasting rats.
10. Within 48 hr after a single administration to non-fasting male rats, the biliary excretion of the radioactivity amounted to 4.5% About 50% of the radioactivity excreted in the bile was attributable to EM-FU.
11. Plasma protein binding in vitro of EM-FU was 34-46% for rats, 47-51% for dogs, and 27-38% for humans; that of 5-FU was 14-21% for rats, 16-17% for dogs, and 14-17% for humans; and that of CNDP was 53-58% for rats, 63-71% for dogs, and 67-69% for humans. Plasma protein binding of total radioactivity in vivo, 4 and 24 hr after a single administration to rats, were 39 and 93%, respectively.

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The matabolic fate of NC-1300-O-3, a new proton pump inhibitor with potent cytoprotective effect on the gastric mucosa, was investigated after a single oral administration of ¹⁴C(Iz)-NC-1300-O-3 or ¹⁴C(Bz)-NC-1300-O-3 to rats and male beagle dogs.
1. The radioactivity in blood and plasma after administration of ¹⁴C(Iz)-NC-1300-O-3 to male rats at doses of 10, 30 and 100 mg/kg reached maxima within 5 hr and thereafter declined. The values of Cmax and AUC were proportional to administered doses, while the difference was observed in disappearance of radioactivity, the elimination half lives of radioactivity in the blood were prolonged compared with those in plasma. No marked differences in pharmacokinetic parameters were observed between male and female rats.
In dogs, the levels of radioactivity in the blood and plasma reached maxima at 2 hr after administration of¹⁴C(Iz)-NC-1300-O-3 at a dose of 30 mg/kg and there after declined biphasecally, and the slow elimination half-life in blood radioactivity, but less compared to rats, was also observed.
When the ¹⁴C(Bz)-NC-1300-O-3 was administered to male rats, the levels of radioactivity in the blood and plasma were 2-7 times lower than those following ¹⁴C(Iz)-NC-1300-O-3 administration at the same dose level. However there was almost no difference between the pharmacokinetic parameters derived from the blood and plasma.
2. High levels of radioactivity were observed in the liver, kidney and gastrointestinal tracts after administration of ¹⁴C-NC-1300-O-3 to male rats. When administered the ¹⁴C(Iz)-NC-1300-O-3, a high radioactivity in the thyroid was observed. However there was no evidence of an accumulation of radioactivity, excluding blood.
3. The protein binding of ¹⁴C(Iz)-NC-1300-O-3 in vitro was more than 98.8% in rat, dog and human plasma. The binding of radioactive substances tc plasma proteins after oral administration of ¹⁴C-NC-1300-O-3 was 72.8-87.4% in rats, 61.7-77.5% in dogs, respectively.
4. The ratio of blood to plasma concentration after addition of ¹⁴C-NC-1300-O-3 to rat blood was increased with time, but almost no changes were observed in the blood of dog, monkey and human.
5. Within 168 hr after oral administration of ¹⁴C(Iz)-NC-1300-O-3 to male rats, 69.7 and 26.8% of the dose were excreted into urine and feces, respectively. On the other hand, 30.6 and 67.7% of the dose were excreted into urine and feces in case of ¹⁴C (Bz)-NC-1300-O-3. After administration of ¹⁴C(Iz)-NC-1300-O-3 and ¹⁴C(Bz) -NC-1300-O-3 to bile duct-cannulated male rats, 41.1 and 77.0% of the dose were excreted to bile within 48 hr, respectively, and approximately 80% of excreted radioactivity to bile was reabsorbed by entero-hepatic circulation.
In dogs, the main excretion route was feces, 64.0 or 91.2% of the dose was excreted into feces within 168 hr after administration of ¹⁴C(Iz)-NC-1300-O-3 or ¹⁴C(Bz)-NC-1300-O-3.

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The metabolic fate NC-1300-O-3, a new proton pump inhibitor with potent cytoprotective effect on the gastric mucosa, was investigated after daily oral administration of ¹⁴C(Iz)-NC-1300-O-3 (30 mg/kg) for 28 days to male rats. The transfer of radioactivity into fetus and milk was also investigated after a single oral administration (30 mg/kg) to pregnant and lactating rats.
1. The levels of radioactivity in the blood at 24 hr after daily administration rose as number of doses increased, and the concentrations after 28th dose were 9 times higher than those after the first dose. While the levels of radioactivity in the plasma did not change during dosing period. Disappearance of radioactivity from blood following 28th dose was similar to that after a single dose.
2. The distribution of radioactivity in the tissues was measured at 24 hr after the 1st, 7th, 14th, 21st and 28th dose, the radioactivity accumulated throughout the dosing period in most tissues. In the blood, epididymis, spleen and heart after 28th dose, the radioactivity levels rose greatly, and were 11.3-8.0 times higher than those of the first dose, while the radioactivity levels in the other tissues were less than 7 times.
3. The excretion of radioactivity in urine and feces reached near steady state after 2nd dose. Within 168 hr after the 28th dose, urinary and fecal excretion amounted to 60.6 and 39.2% of cumulative dose, respectively.
4. The radioactivity levels in the fetus on day 13 of gestation were less than 40% of the maternal plasma levels at every time point, indicating a low placental transfer. However, on day 18 of gestation, the radioactivity levels in the fetus were nearly equal to those in maternal plasma.
5. The concentrations of radioactivity in the milk were 3-9 times higher than those in plasma at every time point studied.

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The metabolism of NC-1300-O-3, a new proton pump inhibitor with potent cytoprotective effect on the gastric mucosa, was examined after oral administration of ¹⁴C-NC-1300-O-3 in rats and dogs.
1. Following metabolites were found to be present in rat plasma, urine, bile and feces as well as in dog plasma and urine after oral administration of ¹⁴C(Iz)-NC-1300-O-3; 2-mercaptobenzimidazole (MBI), 5-hydroxy-2-mercapto-l-benzimidazole (MBI-OH), benzimidazole (BI), 5-hydroxy-1H-benzimidazole (BI-OH), 2-[[2-(isobutylmethylamino)benzyl]thio]-1H-benzimidazole (NC-1300-O-3 sulfide).
2. Following metabolites were identified in rat urine and bile after oral administration of ¹⁴C(Bz)-NC-1300-O-3; 2-(isobutylmethylamino)benzyl alcohol (BMABA), 3-[N-(2-hydroxymethyl) phenyl-N-methylamino]-2-methylpropanol (HPAPOL), 3-[N-(2-hydroxymethyl) phenyl-N-methylamino]-2-methyl propionic acid (HPAPA).
3. In rat and dog plasma after administration of ¹⁴C(Iz)-NC-1300-O-3 or ¹⁴C (Bz)-NC-1300-O-3, the major metabolites were MBI and BI, while very little unchanged NC-1300-O-3 was found. Conjugates of MBI-OH, BI-OH and HPA-PA were mainly excreted to the urine in rats, while conjugate of BI-OH was a main metabolite excreted to urine in dogs. In rat bile, the major metabolites were conjugates of MBI-OH, MBI and BMABA.
4. NC-1300-O-3, NC-1300-O-3 sulfide and MBI-OH were mainly found in rat feces after administration of ¹⁴C(Iz)-NC-1300-O-3.
5. In the plasma, urine and feces after the 28th administration of ¹⁴C(Iz)-NC-1300-O-3 to rats, the composition of NC-1300-O-3 and its metabolites was almost similar to that after a single dose.

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