Time courses of plasma levels were examined using two-steps enzyme-immunoassay(EIA) in rats and dogs after single intravenous or subcutaneous injection of recombinant human erythropoietin (SNB-5001). After intravenous injection of SNB-5001 to rats and dogs, the plasma level declined biexponentially, well described by a two-compartment model. Plasma half lives of rapid phase and slower phase were 0.7 ?? 1hr(t_1/2α) and 1.8 ?? 6hr(t_1/2β) in rats, and 1 ?? /1.7hr (t_1/2α) and 4.3 ?? 10.1hr (t_1/2β) in dogs, respectively, after single intravenous injection in dosing range from 50 to 1250U/kg of SNB-5001. Plasma level profiles in female dogs were similar to those in male dogs after intravenous injection of SNB-5001. After the subcutanous injection of SNB-5001, plasma levels gradually increased showing a dose-dependent C_max values. T_max was 6 ?? 7hr in rats and 7 ?? 13hr in dogs. Plasma levels of SNB5001 determined by EIA showed a good correlation with the levels of biological activity determined by in vitro bioassay. Plasma SNB-5001 levels after subcutaneous injection declined slower than those after intravenous injection in rats and dogs. Plasma half lives in dogs were longer than those in rats after both intravenous and subcutaneous injection of SNB5001. The area under the plasma concentration-time curve increased in dose-dependent manner after intravenous and subcutaneous injection of SNB-5001 in rats and dogs. Bioavailabilities after subcutaneous injection were 50 ?? 60% in rats and 40 ?? 70% in dogs.

View full abstract

Pharmacokinetics and accumulation of recombinant human erythropoietin (SNB-5001) were studied in rats after the intravenous(i.v.) and subcutaneous injection(s.c.) of ¹²⁵I-SNB-5001. Plasma level declined biexponentially with a rapid phase (t_1/2α : 0.4 ?? 0.9hr) and a slower phase (t_1/2β :3.0 ?? 5.2hr) in male and female rats after a single i.v. (50 ?? 1250U/kg). Dosedependent Ccnax was observed at 6 ?? 9 hr after s.c. Plasma level after s.c. declined slower than after i.v. AUC_0→∞ in rats after both injections increased in dose-dependent manner. Bioavailabilities after s.c. were 65 ?? 75%. Maximal levels of radioactivity in most tissues were observed at 10 min ?? 1hr after i.v. and at 6 ?? 12 hr after s.c. Higher radioactivity was found in the plasma and bone marrow following by kidney, liver and spleen. It was difficult to find the radioactivity in the brain and fat tissue. The decrease of tissue levels was proportional to that in the plasma. The levels in plasma and bone marrow at 24 hr after s.c. were two-fold higher than those after i.v. Urinary excretion of radioactivity was about 80% of injected dose in male and female rats until 96hr after i.v. Fecal excretions until 96hr accounted for 6% of administered dose, similar results were observed in rats after s.c. Biliary excretion was 7 % in male rats until 48 hr after i.v. A small amount of high molecular weight radioactive compound was observed in the urine and bile just after the injection, and other consisted of a low molecular weight radioactive compounds as revealed by HPLC analysis. During the repeated injection (50U/kg), the plasma levels at 1 hr after each i.v. and at 6 hr after each s.c. remained almost constant since the first day. There were no pronounced differences in pharmacokinetics between single and repeated injection (for 7 days) as measured the immunoreactive radioactivity. Plasma levels of total and TCA-precipitable radioactivity declined slower than those after the single injection. The tissue levels at 24hr after repeated injection increased than those after single injection but the ratios of tissue to plasma level after repeated injection scarcely changed. The excretion rates in urine and feces were nearly constant during the period of repeated injection, and 80% of injected radioactivity was recovered in urine and 8% in feces until 96hr after the last injection. Free ¹²⁵I and high molecular weight metabolites were observed in plasma and tissues as determined by HPLC analysis. Free ¹²⁵I gradually increased as the levels of ¹²⁵I-SNB-5001 decreased. High molecular weight metabolites, such as M-3 in the plasma and M-1 in tissues, had a slight immunoreactivity. The immunoreactive metabolites were not detected in thyroid. These metabolites present in plasma, tissues and urine after repeated injection were almost same as those after a single injection. It was suggested that there was no specific tissue accumulating SNB-5001.

View full abstract

Absorption, distribution, metabolism and excretion were investigated after a single oral administration of ¹⁴C-Felodipine 1 mg/kg to rats of both sexes.
1. The blood concentration of radioactivity in male rats reached the C_max of 1, 760ng eq./ ml at 2hr and then declined with half-lives of 10hr up to 48hr and 45hr from 72hr to 168hr. The AUC was similar to that after intravenous administration. The blood concentration in female rats reached the C_max of 1, 612ng eq./ml at 12hr and then declined with a half-life of 24hr up to 168hr. While the C_max were similar in male and female rats, the AUC was 1.9 times higher in females.
2. In male rats, 41.3, 53.7 and 2.1% of the dose was excreted in the urine, feces and expired air, respectively, within 168hr. 54.5 and 11.1% of the dose were excreted in the bile and urine, respectively, within 48hr. 50.9 and 15.5% of the injected biliary radioactive materials were re-excreted in the bile and urine, respectively, within 48hr. In female rats, 61.0, 34.3 and 0.8% of the dose were excreted in the urine, feces and expired air, respectively, within 168hr. And 44.9 and 28.0% of the dose were excreted in the bile and urine, respectively, within 48hr.
3. The majority of tissues in male rats showed a maximum radioactivity concentration 2hr after administration. At the maximum, plasma, liver and blood exhibited high radioactivity, but other tissues showed less than 59% of the radioactivity found in the plasma. Radioactivity of all the tissues decreased to less than 5% of the maximum 168hr after administration. The majority of tissues in female rats also showed a maximum radioactivity 2hr after administration. T/P ratios were similar in male and female rats, except for lower ratio in the liver of females. The elimination of radioactivity from tissues was similar in male and female rats, except for slower elimination from the blood and plasma of females.
4. In the urine the mono acid form M-III and M-IV were mainly found. In the bile M-III, MB3, MB4 and M-IV were present principally as free or conjugate forms. The relative amount of M-III was significantly less and the relative amount of M-IV conjugate was slightly greater in female rats. In the plasma, M-IV, M-III and MB5 were mainly found. The relative amount of MB5 was significantly higher and the relative amount of M-III significantly lower in female rats.
It can be supposed that some sex difference is present in metabolic fate of Felodipine in rats.

View full abstract

The absorption, distribution, metabolism, and excretion of ₁₄C-Felodipine were investigated during and after its repeated oral administration to male rats at a daily dose of 1mg/kg for 28 days.
1. The concentration of radioactivity in the blood (24hr after daily dosing) almost reached a steady state after the 25th dosing and was 1.9 times higher after the 28th dosing than that found after the 1st dosing. The C_max after the 28th dosing was 1.3 times higher than that in the single dosing. The half-life up to 48hr was 1.4 times longer and the half-life from 72hr to 168hr was 2.2 times longer than that found in the single dosing.
2. The excretion of radioactivity in the urine and feces reached almost a steady state by the 14th dosing.
3. Most of the tissues tended to reach a steady state by the 14th dosing. The disappearance of radioactivity after the 28th dosing was slower than that in the single dosing. The fractionation of radioactivity in the fat 168, 336 and 1, 008hr and liver 168hr after the 28th dosing suggested that radioactivity in the fat and liver was not due to the metabolites of Felodipine but due to the labelled carbon which is taken up by biological components.
4. The relative amounts of metabolites in the plasma and urine did not change with repeated dosing.

View full abstract

The distribution of radioactivity in fetuses and the transfer to milk were investigated after oral administration of ¹⁴C-Felodipine 1mg/kg to pregnant or lactating rats. Distribution in blood cells and the protein binding of radioactivity were also studied.
1. In a study of gastro-intestinal absorption in situ, the largest amount of ¹⁴C-Felodipine was rapidly absorbed from the small intestine, in addition, absorption also occured from the stomach and large intestine.
2. The distribution ratio of radioactivity in blood cells was less than 2% from 30min to 8hr after oral administration to male rats.
3. The protein binding ratios (in vitro) of radioactivity were over 99% in plasma samples of rats, dogs and human at 0.1 ?? 100μg/ml. The binding ratio (in vitro) of radioactivity to human albumin was 97%. In rats, the protein binding ratio (in vivo) of radioactivity was over 99%.
4. On the 12th and 18th days of gestation, the level of radioactivity in the fetus was lower than that in the maternal blood according to whole body autoradiograms. The level of radioactivity in the fetus on the 18th day of gestation was higher than that on the 12th day of gestation. On the 18th day of gestation, most of the fetal tissues showed maximum radioactivity concentrations 12hr after administration. The radioactivity concentrations in fetal tissues were less than 11% of that in the maternal plasma, the radioactivity concentration in brain being especially low. The disappearance of radioactivity from the fetal tissues was slightly slower than that from the maternal body.
5. The radioactivity concentration in milk was 6 ?? 13% of that in the plasma at any time.

View full abstract

Biotransformation of (4R)-3-benzoyl-N-[(1R)-1-phenylethyl]-4-thiazolidinecarboxamide (RS-0481), developed as a host mediated antitumor activator, was studied in rats and dogs. Twelve metabolites, M₁ to M₁₂, were isolated from urine, bile and plasma samples of rats or dogs after oral administration of RS-0481 or ¹⁴C-RS-0481 as a tracer. The structures of these metabolites were characterized by GC/EI/MS and ¹H-NMR, and were comfirmed by comparison with corresponding authentic standards. The applicabilities of LC/APCI/MS for the identification of metabolites and the plausible metabolic pathways in these animals involving stereospecific oxidation of RS-0481 were also discussed.

View full abstract

The absorption, distribution and excretion of DR-3355, a new quinolone antimicrobial agent, were investigated in male rats after a single oral administration of ¹⁴C-DR-3355 at a dose of 20 mg/kg.
1. The radioactivity was rapidly and completely absorbed in rats after an oral administration of ¹⁴C-DR-3355. C_maxs in the blood and serum were attained at 0.5hr reaching concentrations of 2.51 and 3.23μg equiv. to DR-3355/ml, respectively. Blood levels of radioactivity decreased with a half life of 1.7hr, and the concentrations at 24hr were below 0.05μg equiv. to DR-3355/ml.
2. DR-3355 distributed to all tissues except the central nervous system and the adipose tissue. Tissue concentration profiles of radioactivity were almost parallel to that of blood. Autoradiograms showed that radioactivity disappeared from most of tissues at 72hr after administration.
3. Blood cell binding and serum protein binding were almost independent of time, and corresponding binding values were 28 ?? 33 and 40 ?? 51%, respectively.
4. Most of radioactivity was excreted into urine (43.8%) and feces (56.8 %) within 48hr. Cumulative biliary and urinary excretions were 57.4% and 36.8% in bile duct-cannulated rats, respectively. These results indicated that fecal excretion of radioactivity was mainly derived from biliary excretion and radioactivity was reabsorbed by enterohepatic circulation.

View full abstract

The absorption, distribution, excretion and accumulation of DR-3355, a new quinolone antimicrobial agent, were investigated in male rats after repeated oral administrations at a daily dose of 20mg/kg for 21 days.
1. Blood levels of radioactivity at 30min after daily administration were within the range from 1.8 to 3.3μg equiv. to DR-3355/ml for the period of dosing, indicating that no accumulation in blood occurred. At 24hr after daily administration, blood levels of radioactivity were not detected.
2. The tissue levels of radioactivity at 30min after each dosing were almost of the same levels during the period of dosing. Autoradiograms showed that radioactivity did not accumulate in tissues after repeated administration. On the 21st day after repeated administration, the radioactivity in the bone decreased more gradually than that of other tissues.
3. The excretion rates of radioactivity in the urine and feces were constant during the period of administration. Most of administered radioactivity was excreted into urine and feces until 120hr after the last dosing. Cumulative excretions of radioactivity in urine and feces were 32.1 and 63.7%, respectively. These results were almost the same as those after single administration.
4. Blood cell binding and serum protein binding were almost constant for the period of dosing, and the extent of binding to blood cell and serum protein were 50 ?? 55 and 16 ?? 22%, respectively.

View full abstract

The absorption and excretion of DR-3355, a new quinolone antimicrobial agent, were investigated in male dogs after a single oral administration at a dose of 20mg/kg.
1. Blood levels of radioactivity reached a peak at 4hr and C_max was 6.38 μg equiv. to DR-3355/ml. After reaching the C_max, the blood and serum levels were decreased gradually with t_1/2s 8.4 and 8.7hr, respectively. At 72hr after administration, the radioactivity in the blood was not detected.
2. Blood cell binding and serum protein binding were almost constant with time, accounting for 42 ?? 48 and 26 ?? 39%, respectively.
3. Most of radioactivity was recovered into urine and feces within 48hr after administration. Cumulative excretions of radioactivity in urine and feces at 120hr were 54.4 and 39.4%, respectively.

View full abstract

The absorption and excretion of DR-3355 were studied in cynomolgus monkeys after an oral administration of ¹⁴C-DR-3355 at a dose of 20mg/kg. The distribution of radioactivity was also studied in squirrel monkeys by whole body autoradiography after an oral administration of ¹⁴C-DR-3355. The following results were obtained.
1. Blood levels of radioactivity reached the maximum value of 7.76μg/ml at 3hr after administration and was eliminated with a biological half life of 4.5hr until 24hr after administration. The concentration was below detection limit at 48hr after administration.
2. Blood cell binding rate of radioactivity was 37 ?? 48% between 30min and 24hr after administration. There was no time dependent change in the binding extent.
3. Serum protein binding of radioactivity was 14 ?? 24% throughout the measurement period and there was no tendency to increase binding during observation time.
4. Cumulative excretions of radioactivity within 168hr after administration were 86.1% and 5.0% of administered dose in urine and feces, respectively.
5. DR-3355 distributed into all tissues except central nervous system. Autoradiograms showed that radioactivity disappeared from most of tissues within 30 days after administration. The accumulation of radioactivity in the melanin containing tissues such as hair follicles and uveal tract was observed in the autoradiograms at 30 days after dosing.

View full abstract