To detect the effect of activated charcoal suspension that was perfused in the rat peritoneal cavity, the area under the plasma concentration-time curve (AUC) was determined after a loading of benzoic acid (BA) and salicylamide (SAM) simultaneously to the rat by means of an oral administration in vivo or an intestinal perfusion in situ.
Absorption rate constants (ka) of BA and SAM in situ was not affected by charcoal treatment. AUC of BA remained unchanged following charcoal treatment in comparison to untreated group both in situ and in vivo experiments.
The charcoal treatment significantly decreased the AUC_c-∞ of SAM in both in situ (59.3%) and in vivo (47.3%) experiments as compared with their corresponding controls. These results showed that about a half of SAM absorbed from the intestinal lumen was initially transported to the peritoneal cavity, and then transported to the circulation system.

View full abstract

Pharmacokinetic studies on time-course of blood levels, tissue distribution and excretion of carvedilol, a new β-blocking agent, were performed in rats after a single oral administration of ¹⁴C-carvedilol at a dose of 10mg/kg.
1. The blood concentration of radioactivity showed the remarkable retention due to the high affinity to the erythrocyte, which has been observed only in rats until now.
The plasma concentration of radioactivity reached the Cmax of 713ng/ml(carvedilol equivalent) at lhr and decreased with relatively long half-life of 29.8hr.
2. The radioactivity was relatively well distributed in all the tissues, especially in liver, gastro-intestinal tissues, kidney, harderian gland, lung, hypophysis, submaxillary gland and pancreas. The concentrations in these tissues were 2 ?? 10 times higher than that in the plasma. The concentrations in the other tissues were lower than that in the plasma. The radioactivity in most tissues, except erythrocyte and harderian gland, disappeared in a similar manner as that in the plasma. 3. The radioactivity was excreted during 72hr into urine and feces at the rate of 4.5 and 90.8% of the dose, respectively. The most part of fecal excretion was assumed to be ascribed to biliary excretion.
4. The pharmacokinetic profile of carvedilol was also estimated by whole body autoradiography.

View full abstract

Pharmacokinetic studies on blood level, tissue distribution and excretion of carvedilol, a new β-blocking agent, were performed in rats during and after the consecutive oral administration of ¹⁴C-carvedilol at a daily dose of 10mg/kg for 21 days.
1. The blood radioactivity showed the remarkable accumulation (accumulation factor of 19.0) following the consecutive doses due to the high affinity to the erythrocyte, which was observed only in rats. The plasma concentration of radioactivity reached to the steady state on day 10 and the Css (min) on day 21 was 296ng/ml at the accumulation factor of 4. 1.
2. The radioactivity was well distributed in all the tissues following the consecutive oral doses. The radioactivity in the liver, which was the highest in all of the tissues after a single oral dose, has reached the steady state until day 21 at the accumulation factor of 4.8 in a similar manner as that in the plasma.
The radioactivity in the fat and brown fat increased much greater and disappered much slower than that of plasma.
The remarkable accumulation of radioactivity in spleen was assumed to be ascribed to the high affinity to the erythrocyte.
3. Excretion rates in urine and feces during the consecutive oral doses were nearly constant, and were 3.5 ?? 3.6% and 84.0 ?? 91.6%, respectively. At 48hr after the last dosing, the total excretion into urine and feces was approximately 96% of the dose.
4. The accumulation of radioactivity in tissues was also estimated by whole body autoradiography.

View full abstract

The biliary excretion of the radioactivity was studied following the oral (10 mg/kg) and intraveneous (1.26mg/kg) administration of ¹⁴C-carvedilol to bileduct cannulated rats. Additionally, the enterohepatic circulation of biliary metabolites which were collected from the other rats dosed orally with ¹⁴-Ccarvedilol was investigated in bile-duct cannulated rats.
In the first 2h after intravenous dosing, 76.1% of the administered radio-activity was excreted into the bile. Whithin 48h after dosing, the cumulative excretion of the radioactivity into the bile amounted to 89.9%. The recovery of radioactivity in the urine and feces were 8.1% and 2.2%, respectively. Also after oral dosing, biliary excretion amounted to 84.9% of the administered radioactivity within 48h. The recovery of radioactivity in the urine and feces were 2.9% and 14.1%, respectively. These findings suggest that biliary excretion is the major route of excretion of carvedilol in rat. Judging from the combined recovery in bile and urine after oral dosing, it is clear that at least 87.8% of the oral dose was absorbed.
Intraduodenal injection of the bile collected from other rats dosed orally with ¹⁴C-carvedilol led to excretion of radioactivity into the bile(34.5% of the dose) and urine (5.6%) of the recipient animals. These results showed that enterohepatic circultion was taking place in rats, and that 40.1% of biliary excreta was reabsorbed.

View full abstract

Transfer of the radioactivity into the milk was studied after a single oral administration of ¹⁴C-carvedilol at a dose of 10 mg/kg to lactating rats. The concentrations of radioactivity in the milk were higher than that in the plasma throughout the experimental period. The disappearance of the radioactivity from the milk was slower than that from the plasma and the milk-to-plasma concentration ratio reached the value of 7.3 at 8h after dosing in lactating rats.

View full abstract

The transport of carvedilol to fetuses via placenta was studied in pregnant rats on days 12 and 19 of gestation after a single oral administration of ¹⁴C-carvedilol at a dose of 10mg/kg.
1. On day 12 of gestation, the concentrations of radioactivity in the fetus were lower than that in the maternal blood as determined by liquid scintillation counting and autoradiography. The percentage distribution of radioactivity in a fetus amounted to less than 0.01% of dose.
2. On day 19 of gestation, the concentrations of radioactivity in fetal plasma, fetal blood and fetal liver at 1 hr were nearly half as high as that in the maternal plasma. The percentage distribution of radioactivity in a fetus amounted to 0.01% of dose.
Biliary excretion in fetus was suggested from the observation of relatively high concentration of radioactivity in fetal intestine at 24hr. It was concluded that the transfer of carvedilol into fetus was low.

View full abstract

The absorption and excretion of ¹⁴C-carvedilol were studied in cynomolgus monkeys after an oral administration of ¹⁴C-carvedilol at a dose of 10 mg/kg. The distribution of radioactivity was also studied in squirrel monkeys by whole body autoradiography after an oral or intravenous administration of ¹⁴C-carvedilol.
Blood level reached to the maximum of about 2.3μg eq./ml at 2h after an oral administration and decreased with the terminal half-life of 31.3h. The concentration of the radioactivity in plasma was higher than that in blood throughout experimental period. It was suggested that the erythrocyte binding in cynomolgus monkeys was clearly low as contrasted with that in rats. After an oral administration of ¹⁴C-carvedilol to cynomolgus monkeys, approximately 65% and 16% of dose were excreted within 10 days into feces and urine, respectively.
In the whole body autoradiograms after an oral or intravenous administration to squirrel monkeys, high levels of radioactivity were observed in the gall bladder, liver, intestinal contents. It was suggested that biliary excretion was a major elimination route of carvedilol in monkeys. The distribution of radioactivity to tissues after an oral administration was remarkably low in comparison with that after an intravenous administration.
The accumulation of radioactivity in hair follicles and uveal tract containing melanin were observed in the autoradiograms at 24h after dosing.

View full abstract

The causes of the difference in the permeability from the intestinal lumen to the serosal compartment between salicylamide(SAM)and benzoic acid(BA) has been studied from the point of view of the plasma protein-binding, the blood-to-plasma concentration ratio (R_BP), the pH effect and the solvent drag effect. Latter two effects were also tested for salicylic acid (SA), p-hydroxy-benzoic acid (HBA), phenacetin (PHT) and antipyrine (AP).
The protein binding and RBP were not the reason of the difference in the intestinal permeabilities. The effects of pH and tonicity of the perfusion solut ion on the drug permeability into the blood (CL_B) and into the serosal compartment (CL_S) were determined. CL_S of SAM and CL_B of BA obeyed the pH partition theory. But, CL_B of SAM and CLs of BA was not affected by the pH. Tonicity also did not significantly affect the permeabilities of SAM to the blood and to the serosal compartment. However, CL_B of BA was incr eased by the hypotonicity indicating the existence of the solvent drag effect. CL_S of BA was not affected by the tonicity. SA and HBA showed the same character as BA. PHT and AP had a considerable permeability to the serosal compartment and AP was reported to be transported to the serosal compartment.
It was concluded that BA as well as SAM permeated the mucosal membrane of intestinal cells, and then they were transported to the blood or to the serosal compartment. The ratio of BA transported to the blood/to the serosal compartment was much larger than that of SAM. BA was transported to the blood by the solvent drag, while SAM was not. Consequently the portion of BA transported to the serosal compartment was little, while that of SAM was considerable. This discrepancy was caused by the characters of drug ; such as 1) the permeability of the serosal membrane of the intestine, 2) the liability to be carried by the solvent drag.

View full abstract

Beraprost sodium (TRK-100 : Sodium (±)-(1R*, 2R*, 3aS-, 8bS-)-2, 3, 3a, 8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta [b] benzofuran-5-butyrate) labeled with tritium was orally and intravenously administered to male and female rats to examine plasma level profile and metabolism.
After oral administration at doses of 0.04, 0.2 and 1.0mg/kg to male rats, concentration of the unchanged drug achieved maxima at 10-30min (18.4 ± 11.4, 42.7 ± 15.9 and 220.5 ± 68.5ng/ml, respectively), and then declined biphasically. AUC at a dose of 0.2mg/kg was 98.2 ± 23.7ng • hr/ml, which accouted for 81% of AUC after intravenous injection at the same dose. In female rats, higher concentrations were observed than in male.
Metabolites found in plasma were 2, 3-dinor-beraprost, 13, 14-dihydro-l5-oxo-beraprost and 13, 14-dihydro-2, 3-dinor-15-oxo-beraprost. Among the three metabolites, the 2, 3-dinor-beraprost showed the highest AUC and C_max, and thus seemed to be a major metabolite of beraprost sodium.

View full abstract

Absorption, distribution and excretion of ³H-beraprost sodium were studied in rats.
In situ absorption study showed that ³H-beraprost sodium was recadily absorbable from the small intestine. Beraprost sodium inhibited the gastric emptying of ¹⁴C-PEG. However, this effect may result in successive effusion of ³H-beraprost sodium from the stomach and rather contribute to the following maintenance of tissue and blood levels after p. o. dosing. The quantitative distribution studies in male rats suggested the possibility of extensive metabolism in the liver, and the following biliary excretion and enterohepatic circulation. Excretion in the urine and feces was rapid and almost complete after both p. o. and i. v. dosing to male and female rats. Irrespectively of dosing route, male rats excreted about 85% of the dose in the feces. whereas the female rats excreted near to a half of the dose in the urine. It therefore can be supposed that some sex difference is present in the biotransformation of beraprost sodium in rats. The elimination with the expired air, placental transfer, transfer to the suckling pups via the milk and melanin affinity were not signficant.

View full abstract

The metabolites of beraprost sodium in plasma and tissues, and its biliary excretion and enterohepatic circulation were investigated in male and female rats using ³H-labelled substance.
The most predominant metabolite, 2, 3-dinor-beraprost was shown to be distributed mainly in the liver. However, this β-oxidation metabolite was found to be produced in male rats at an apparently higher level than in female rats. On the other hand, as the oxidation of C-15 alcohol is concerned, the females possess higher capacity for this biotransformation process. The study on biliary excretion showed that male rats could excrete more drug, principally as 2, 3-dinor-beraprost, into the bile compared to the female rats. This sex difference in biliary excretion was facilitated by the following enterohepatic circulation. As a result, urinary excretion of beraprost sodium in female rats attained nearly four times of that in male rats.
All these results seem to be basically related to the difference in β-oxidation capacity in the liver of both sexes.

View full abstract

After oral administration of ³H-beraprost sodium to male rats at a dose of 1.0mg/kg, metabolites in urine and feces were analyzed by HPLC, and the structures of nine metabolites were determined by NMR spectroscopy, mass spectrometry and comparative HPLC with synthetic standards.
The structures of the metabolites suggest metabolic pathway of beraprost sodium involving β-oxidation, oxidation of hydroxyl group at C15-position, hydrogenation of double bond and oxygenation at ω-side chain. Major metabolite in urine and feces was 2, 3-dinor-beraprost, a product of β-oxidation of beraprost sodium (11.26% of the dose in urine and 43.21% of the dose in feces).

View full abstract

The plasma levels of beraprost sodium and its major metabolites were determined in dogs after oral administration of ³H-labeled beraprost sodium.
The major metabolites in the dog plasma were found to be 13, 14-dihydrol-15-oxo-beraprost, 2, 3-dinor-beraprost and 13, 14-dihydro-2, 3-dinor-15-oxo-beraprost as determined by co-chromatography with synthetic reference standards on high-performance liquid chromatography. The plasma concentration of unchanged beraprost sodium increased rapidly, reaching a maximum concentration 20 to 25min (mean value) in males and 10 to 24min (mean value) in females after dosing of 0.008, 0.04 and 0.2mg/kg, and then declined thereafter with a biphasic pattern. The metabolites appeared in the plasma rapidly after dosing and the major metabolite was 13, 14-dihydro-15-oxo-beraprost in both males and females.

View full abstract

The excretion and metabolism of beraprost sodium were investigated in dogs after oral administration of ³H-labeled beraprost sodium.
In males, the orally administered radioactivity was excreted into urine and feces in 14.7% and 73.8% of administered dose, respectively, within 72hrs after dosing. In females, 17.6% and 69.6% of the dose were excreted into urine and feces, respectively.
Beraprost sodium was metabolized by various reactions involving β-oxidation of α-side chain, reduction of C-13 double bond, oxidation of C-15 hydroxy group, ω-oxidation of ω-side chain and taurine conjugation. The major metabolites in urine and feces were 2, 3-dinor-beraprost and 13, 14-dihydro-2, 3-dinor-15-oxo-beraprost, accounting for 25.77% and 9.31% of the total dose in males, and 26.80% and 9.80% in females, respectively, as determined by HPLC. Identified metabolites accounted for 67.23% of the dose in males and 68.84% in females, respectively.
No difference was observed in excretion as well as metabolism between male and female dog.

View full abstract

Plasma levels, distribution, excretion and metabolism of [¹⁴C] zonisamide was studied in rats of different age (1-, 14-, 28 and 49-days old).
After oral administration of 20mg/kg to 1-and 14-days old rats, the elevation of plasma levels was slightly delayed in comparison with rats of other ages. However, maximal plasma levels were similar to each other (13-18μg eq. /ml) in all ages studied. Disappearance half life of plasma radioactivity in 1-day old rats was 133 hr, which was markedly longer than that in elder rats(6-12 hr). Zonisamide concentration in erythrocytes was lower in younger rats. This was found to be correlated with the activity of erythrocyte carbonic anhydrase, a component for zonisamide binding. Radiometric and autoradiographic studies revealed that distribution pattern of radioactivity in tissues was similar to each other in all ages studied. Radioactivity was mostly excreted in urine of 14-, 28 and 49-day old animals. Composition of urinary metabolites was qualitatively similar to each other in 14-, 28-and 49-day old rats but from quantitative point of view was different.

View full abstract