Pharmacokinetic study on CPT-11, a new antitumor agent, was performed in female rats by the measuring of radioactivity after a single intravenous administration of ¹⁴C-CPT-11 at a dose of 10mg/kg.
1. Within 72 hours after administration, 98% of radioactivity was excreted (urine 18.7%, feces 79.3%). No difference was observed in the rate or extent of excretion of CPT-11 between male and female rats.
2. Whole blood level in female rats was almost the same as that in male rats within 8 hours after administration but was slightly higher between 24-72 hours after administration.
3. Tissue concentration in female rats were almost of the same levels as those in male rats.
4. CPT-11 was distributed to ovary or uterus rapidly and highly. Tissue/plasma ratios in these organs were 1.71 ?? 5.94, 1.29 ?? 4.31, respectively.
5. From above results, a minimal difference was observed in pharmaco kinetics of CPT-11 in male and female rats. It is also suggested that CPT-11 can be used in the treatment of gynecological tumors.

View full abstract

The transport of CPT-11 to fetuses via placenta was studied in pregnant rats on days 13 and 18 of gestation after a single intravenous administration of ¹⁴C-CPT-11 at a dose of 10mg/kg.
1. On day 13 of gestation, the levels of radioactivity in the fetus were lower than that in maternal blood as determined by liquid scintillation counting and autoradiography. The percentage distribution of radioactivity in a fetus only amounted to less than 0.01% of administered dose.
2. On day 18 of gestation, the levels of radioactivity in fetal liver at 5min and lhr were similar to those in the maternal plasma. The radioactivity in fetal blood and other tissues at 5min and 1hr were than those in the mater nal plasma. The percentage distribution of radioactivity in a fetus amounted to less than 0.07% of dose.
3. The distribution of radioactivity into fetal membrane, placenta, ovary, uterus, clitoral gland and mammary gland in maternal rats were clearly detected in autoradiography.

View full abstract

Transfer of the radioactivity into the milk was studied after a single intravenous administration of ¹⁴C-CPT-11 to lactating rats at a dose of 10mg/kg. The levels of radioactivity in the milk were significantly higher than that in the plasma and the milk-to-plasma concentration ratio reached the maximum value of 64.7 at 4hr after dosing. The disappearance of the radioactivity from the milk was relatively rapid and the milk-to-plasma concentration ratio reached the value of 1.0 at 24hr after administration.

View full abstract

Pharmacokinetic studies on blood level, tissue distribution and excretion of CPT-11, a new antitumor agent, were performed in rats during and after the consecutive intravenous administration of ¹⁴C-CPT-11 at a daily dose of 4mg/kg for 15 days.
1. Blood levels of radioactivity at 24hr after daily dosing increased wit the number of doses. Blood concentrations at 24hr after the last closings of the 5th and 15th dose were 1.8 and 4.4 times higher than blood concentration at 24hr after the first dosing, respectively.
2. Urinary and fecal excretion of radioactivity for 24hr after daily dosing (% of dose) was not significantly changed as the number of doses increased. In the group recieving 5 doses, 24.9 and 71.4% of radioactivity was excreted in urine and feces, respectively, during 72hr after the last dosing.
3. As the number of doses increased, the concentration in m ost tissues, except pancras, increased slowly. After the last dosing, radioactivity tended to be slowly eliminated from the spleen, bone marrow, adrenal, mesenteric lymph node and ileum.

View full abstract

We studied whether CPT-11 had an ability to induce activities of drug metabolizing enzyme system in rats.
1. After administration of CPT-11 at a dose of 0.8 (maximal tolerated dose), 4.0 (minimum toxic dose) and 20.0 (lethal dose for 4 weeks succesive administrations) mg/kg for 5 days, the decrease of body weight and liver weight was dose-dependent while the increase of microsomal protein content was not dose-dependent and disappeared 1 week after withdrawal of this compound.
2. Hepatic content of cytochrome P-450 and b, was unchanged by the administration of the test compound at any dose.
3. Slight decrease in aminopyrine N-demethylase and aniline hydroxylase activities was observed in the highest dosage group. These changes were reversible.
4. In vitro, CPT-11 could not inhibit aminopyrine N-demethylase and aniline hydroxylase activities in liver miorosomes obtained from untreated, phenobarbital and 3-methylcholanthrene treated rats.
From these results, we conclude CPT-11 dose not affect the drug metabolizing enzyme system.

View full abstract

The absorption, distribution and excretion of isosorbide dinitrate (ISDN) were studied after application of ¹⁴C-labeled ISDN tablet (¹⁴C-TYB-3215) to the gingiva of male dogs.
1. The level of radioactivity in the plasma reached a maximum 4hr after application and decreased to 1 % of the maximum 48hr after application.
2. Distribution of radioactivity 1 and 4hr after application was high in the kidney, liver, mandibular gland and nasal cavity.
3. Within 120hr after application, 98.9% of the dose was excreted in the urine and 2.2% of the dose in the feces.

View full abstract

To evaluate the stability of liposomes in vivo is an important issue in the kinetic analysis of liposomes disposition, because the leakage of liposomal marker occurs in vivo blood circulation and this leads to incorrect measurement of blood concentration of intact liposomes. In this study, we developed novel quantitative method for the evaluation of the stability of liposomes in blood circulation based on the clearance concept for liposomal degradation. Inulin was used as an aqueous marker of liposomes, because it is impermeable through a biological membrane and is rapidly excreted solely by glomerular filtration. We have further examined the effect of time delay of inulin during the passage of ureter to bladder on the estimation of the free fraction, using deconvolution method. The results showed that this delay was small enough to be neglected in the practical calculation. The degradation clearance of the liposomes in in vivo study was calculated as [f/(1-f)·GFR], where f, GFR are the fraction of free concentration of inulin in blood, and glomerular filtrationr ate. On the other hand, the degradation clearance of the liposomes in in vitro study was calculated as(dose/AUC), where AUC was the area under the time course of the concentration of intact liposomes from t=0 to infinite. The in vivo clearance was 0.0214ml/min, while in vitro one was 0.00103ml/min. There was about 20-fold difference. It shows that the in vitro data is not appropriate for the ananlysis of in vivo data. This method of evaluation of liposome stability in vivo is simple and useful in the pharmacokinetic study of liposomes.

View full abstract

The absorption, distribution, metabolism and excretion of ¹⁴C-labelled Sodium 5-(acetylamino)-3, 5-dideoxy-D-glycero-D-galacto-2-nonulosonate (KI-111) were studied in rats following the intratracheal administration.
The half-life of pulmonary absorption of KI-111 was 1.42 hour and the elimination half-life of KI-111 estimated from the urinary excretion data was found to be about 1.44 hour. The plasma levels of radioactivity reached the maximum at 1.5 hour after administration of KI-111. The peak concentration of the compound in the plasma was observed at 1.5 hour after administration, and then decreased with a half-life of 3.7 hours.
The compound was excreted mainly in the urine. Within 24 hours, the urinary excretion amounted to 99.8% of the dose. Within 6 hours, a biliary excretion was not observed. Metabolites in the urine were analyzed by HPLC. Ninety eight % of the radioactivity present in the urine was recovered as the unchanged compound and 2 % of as N-acetylmannosamine.
After the intravenous administration of KI-111 to rats, the plasma levels of KI-111 decreased biphasically with a corresponding half-lives of 1.5 minutes and 22.4 minutes. And three hours after i.v. administration, the KI-111 was not detected in the plasma.

View full abstract

Placental transfer and mammary excretion of radioactivity were investigated in pregnant rats and lactating rats after intravenous administration of ¹⁴C-labelled Sodium 5-(acetyl-amino)-3, 5-dideoxy-D-glycero-D-galacto-2-nonulosonat (KI-111).
Placental transfer was investigated on day 13 and 19 of pregnancy by measurement of tissue level, and by whole body autoradiography(WARG) on day 19 of pregnancy. Five minutes after administration of KI-111, the radioactivity was observed in the all tissues and organs except the fetuses as revealed by the WARG. Regarding the tissue levels of KI-111 in day 13 and 19 pregnant rat, no radioactivity was detected in the fetuses within 1.5 hour after administration, though 24 hours after administration, small amount of radioactivity was de tected in the whole fetus of day 13 pregnant rat. No radioactivity was detected in the fetal organs 5 to 45 minutes after administration, however, small amount of radioactivity was detected in the fetal brain and fetal intestine in the day 19 pregnant rat during 1.5 to 24 hours after administration.
Radioactivity excreted into the milk was determined on day 10 to 12 after parturition. The highest concentration of radioactivity in the milk was observed at 1.5 hour after administra tion, but the amount was small.

View full abstract

Accumulation and elimination of ¹⁴C-labelled Sodium 5-(acetylamino)-3, 5 dideoxy-D-glycero-D-galacto-2-nonulosonate (KI-111) were studied in rats after 7 or 14 repeated subcutaneous (s.c.) administration, by measurement of the tissue level and whole body autoradiography. At 15 minutes after final s. c. administration of the compound, the radioactivity was observed in all tissues and organs except the brain and spinal cord. High radioactivity was observed in the injected site, kidney and circulating blood. At 24 hours after administration, the radioactivity was observed in the injected site, kidney and intestine.

View full abstract

The metabolic fate of ¹⁴C-labelled Sodium 5-(acetylamino)-3, 5-dideoxy-D-glycero-D-galacto-2-nonulosonate (KI-111) has been investigated following oral administration. KI-111 administrated orally was excreted in urine (6%), feces (30%) and expired air (62%) within 72 hours after administration. KI-111 was thought to be metabolized by intestinal flora to CO₂, therefore an in vitro study was conducted to confirm that assumption. Intestinal content of rats was collected sterilely and incubated with ¹⁴C-labelled KI-111 under nitrogen atmosphere. Twenty percent of the added radioactivity was detected in the excreted ¹⁴C0₂.This result showed that KI-111 was metabolized by intestinal flora to CO₂.

View full abstract

The absorption, distribution and excretion after oral or intravenous dosing of TA-870 (30mg/kg, 64μmol/kg) and dopamine (DA) (12mg/kg, 64μmol/kg) were studied in rats or dogs.
1) Absorption of ³H-TA-870 from digestive tract in male rats was higher than that of ³H-DA.
2) Plasma levels of radioactivity after oral administration of ¹⁴C-TA-870 and ¹⁴C-DA to male rats reached the peak at 1.0hr and thereafter decreased with half-lives of 3.0 and 3.6hrs up to 24hrs, respectively.
3) Peak concentrations of radioactivity in rat tissues after oral dosing of ¹⁴C-TA-870 were higher than those after administration of ¹⁴C-DA.
4) Excretion rates of radioactivity in urine and feces within 72hrs after oral administration of ¹⁴C-TA-870 were 82.3 and 17.6%, respectively, in male and 79.6 and 15.5%, respectively, in female rats. Excretion within 72hrs after oral administration of ¹⁴C-DA to male rats was 71.5% in urine and 24. 1% in feces. Excretion up to 72hrs after intravenous dosing to male rats was 92.1% in urine and 8.0% in feces. Urinary and fecal excretion rates within 72hrs after oral dosing of ¹⁴C-TA-870 to male dogs were 56.4 and 37.4%, respectively.
5) Biliary excretions of radioactivity within 24hrs after oral administration of ¹⁴C-TA-870 and ¹⁴C-DA to male rats were 19.8 and 12.6%, respectively. It was found that 76% of the radioactivity excreted in bile was reabsorbed, as revealed by the enterohepatic circulation study.
6) Labelled positions of ¹⁴C-TA-870 and ³H-TA-870 were stable in the in vivo studies using rats.

View full abstract

Absorption, distribution and excretion of TA-870 were investigated in male rats after single and repeated oral administration at a dose of 30mg (64μmol)/kg/day.
The blood level of radioactivity at 1 hr (T_max) after dosing reached a steady state in the early stage of repeated dosing and did not increase significantly thereafter. There was no significant difference in pharmacokinetic parameters of the drug between single and repeated dosing.
The radioactivities in tissues at 1 hr after repeated dosing were similar to those after single dosing. However, the levels of radioactivity at 6 ?? 48hr after repeated dosing were higher than those after single dosing.
The excretion of radioactivity in the urine and feces was nearly constant during repeated dosing of ¹⁴C-TA-870 and the recovery was 97.5% of total dose.

View full abstract

Foeto-placental transfer and excretion of radioactivity into the milk after oral administration of ¹⁴C-TA-870 at a dose of 30mg (64μmol)/kg were investigated in the pregnant and lactating rats.
The distribution patterns of radioactivity in the pregnant and lactating rats after dosing of ¹⁴C-TA-870 were similar to those of male and normal female rats¹⁾.
Both in fetus and suckling, the radioactivity transferred from maternal rats was lower than 0.05% of administrated radioactivity and did not remain in their organs and tissues at 24hr after oral administration.

View full abstract

The protein binding of TA-870 was investigated in human, dog and rat plas ma with centrifugal ultrafiltration method.
The in vitro binding extent of TA-870 to dog and human plasma were 52-56 and 41%, respectively. The binding extent of TA-870 to human plasma was not influenced by other drugs. The binding of TA-870 to purified human albu min, α1-acid glycoprotein and γ-globulin accounted for 56, 47 and 5%, respec tively. The binding extent of radioactive substances to rat plasma, after oral administration of ³H-TA-870, were 26-55%.

View full abstract