Plasma concentration, distribution, and excretion of [¹⁴C]-alendronate after a single intravenous administration were investigated in 7-week old male rats.
1. The plasma levels of radioactivity after administration of 0.05, 0.5, 5 and 15 mg/kg of [¹⁴C]-alendronate declined rapidly with time at each administered dose. The elimination half-lives were 3-10 minutes (from 5 to 30 min) and 27-60 minutes (from 30 min to 2 hr), and no significant difference in the half-lives was observed between the doses.
2. The level of radioactivity in bones and cartilage after administration of 0.05 mg/kg of [¹⁴C]-alendronate was higher than in plasma and noncalcified tissues at any time points measured after dosing. The concentration in vertebra was the highest among bones, followed by long bones (femur, tibia, humerus) and calvaria. The autoradiography of the long bones revealed a higher level of radioactivity was observed in metaphysis and epiphysis than in diaphysis, especially in the area adjacent to growth plate. Therefore, it was suggested that alendronate was distributed well to region of bone with high turnover.
3. The radioactivity in bones reached a peak concentration at approximately 8 hours after administration and then decreased with a half-life of between 65 and 102 days. Moreover, the half-life of the contents of radioactivity in the long bones and vertebra was between 182 and 242 days. This suggested that decrease in the level of radioactivity in bones was mainly due to increase in bone weight with growth, and substantial elimination of the drug was slow in bones. The uptake of alendronate by bones increased in a dose dependent manner in the range of 0.0515 mg/kg.
4. The radioactivity in noncalcified tissues was lower than in bones, and its decrease was rapid.
5. By the 9th day after administration of ¹⁴C-alendronate at 0.05 mg/kg, 37.5% of the dosed radioactivity was excreted in the urine and 0.3% in the feces. Most of the radioactivity in the urine was excreted within 12 hours after administration.

View full abstract

Plasma concentration, distribution, and excretion of [¹⁴C]-alendronate were investigated after repeated intravenous administration once a day for 7 days to 7-week old male rats and after a single intravenous administration to 30-week old male rats. Feto-placental transfer in pregnant rats and the transfer into the milk in lactating rats were also investigated.
1. The plasma radioactivity after repeated administration at 0.05 mg/kg of [¹⁴C]-alendronate to 7-week old male rats was higher than in single administration. However, there was no difference in the half-lives. The level of radioactivity in noncalcified tissues after repeated administration were also higher than in a single administration, but no accumulation was observed. The maximum level of radioactivity in bones was 6.2-7.5 times higher than in a single dose experiment. The concentration in vertebra was the highest among bones, followed by long bones (femur, tibia, humerus) and calvaria. By the 24th day after final administration, 32.2% of the dosed radioactivity was excreted in the urine and 2.1% in the feces, and the excretion in urine was almost completed within 24 hours. These results suggest that there is no alteration in the disposition of alendronate after repeated administration compared with single administration.
2. The AUC of plasma radioactivity after single administration of 0.05 mg/kg of [¹⁴C]-alendronate to 30-week old male rats was 2 times higher than in 7-week old rats. The radioactivity in the liver, kidneys, spleen, and heart was also higher. The maximum level of radioactivity in calvaria in 30-week old rats were similar to those in 7-week rats, but was approximately 50% lower in vertebra and long bones than in 7-week old rats. Therefore, the difference of concentration among bones in 30-week old rats was less than in 7-week old rats. The cumulative urinary excretion at 216 hours after administration to 30-week rats was higher (46% of dose) than in 7-week old rats. On the basis of these results, it is suggested that the increase of concentration of radioactivity in plasma and noncalcified tissues and urinary excretion in 30-week rats is due to the decrease in the bone uptake of alendronate as a consequence of decline of bone turnover.
3. After single administration of [¹⁴C]-alendronate at 0.05 mg/kg to female rats on day 19 of pregnancy, the concentration of radioactivity in plasma was similar to that of 7-week old male rats. Radioactivity was not detected in fetus, indicating that feto-placental transfer of alendronate was low.
4. After administration of [¹⁴C]-alendronate to female rats 14 days post parturn, the concentration of radioactivity in the milk was higher than in plasma. The transfer of radioactivity into milk was observed.

View full abstract

Plasma concentration, bone distribution, and excretion after single intravenous administration of [¹⁴C]-alendronate to beagle dogs were investigated.
1. The levels of plasma radioactivity after administration of 0.05 mg/kg of [¹⁴C]-alendronate to beagle dogs declined triphasically, and the half-life of each phase was 25 minutes, 1.6 and 12.2 hours, respectively.
2. The cumulative excretion rates of radioactivity within 168 hours after administration of [¹⁴C]-alendronate was 36% of dose in urine and 8% in feces. Radioactivity was mainly excreted in the urine as in the case of rats, and the excretion in urine was almost completed in 24 hours after administration.
3. The levels of radioactivity in bones at 168 hours after administration of 0.05 mg/kg of [¹⁴C]-alendronate was 248.9 to 391.7 ng eq./g in vertebra and long bones, and 40.0 ng eq./g in calvaria. The difference of the concentration among bones was observed as in the case of rats. The autoradiography of the long bones revealed the higher level of radioactivity in the epiphysis and metaphysis than that in the diaphysis. High levels of radioactivity were observed along the growth plate of the long bone. On the basis of these results, it is suggested that alendronate is distributed in bones, especially in the high turnover region.

View full abstract

The pharmacokinetics of finasteride was assessed in 12 elderly and 12 young/ middle-aged volunteers following single oral administration of 5-mg drug.
A plasma concentration profile of finasteride in the elderly is similar to that in young/middle-aged volunteers. Although C_max (39.7 ng/ml) and AUC_0-∞ (267 ng·hr/ml) in elderly volunteers were slightly lower than those (44.7 ng/ml and 318 ng·hr/ml) in young/middle-aged volunteers, there were no significant differences in these parameters between two groups. Also, there were no significant age-related differences in other pharmacokinetic parameters such as T_max MRT and t_1/2.
Urinary concentrations of metabolites, ω-hydroxylated finasteride (M-1) and finasteride ω-oic acid (M-3), were also determined. Metabolite M-1 was not detected in any urine samples. Approximately 26.8% of the dose was excreted in urine as M-3 in the elderly, and 23.1% of the dose in young/middle-aged volunteers.
These results suggest that the metabolism and disposition of finasteride are similar in the elderly and young/middle-aged volunteers after single oral administration.

View full abstract

The concentrations of the metabolites of propiverine hydrochloride (1-methyl-4-piperidyl diphenylpropoxyacetate hydrochloride, abbreviated as P-4) in rat tissues were determined after p.o. administrations. The major metabolites were found to be as follows; 4-piperidyl diphenylpropoxyacetate (DM-P-4), 1-methyl-4-piperidyl benzilate (Dpr-P-4) and 1-methyl-4-piperidyl diphenyl-(2 carboxy) ethoxyacetate (ω-COOH-P-4) in the liver, Dpt-p-4, DM-P-4 in the kidney, and DM-P-4, DPr-P-4 in the lung. The unchanged compound was also detected in the liver, kidney and lung. In all instances, the tissue concentrations were higher than those in the plasma. All pharmacologically active compounds such as the unchanged compound, 1-methyl-4-piperidyl benzilate N-oxide (DPr-P-4 (N→O)), Dpt-p-4 and 1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide (P-4 (N→O)) were present in the urinary bladder, a target organ for P-4, at higher concentrations than in the plasma.

View full abstract

The transfer of finasteride into the fetus and milk was investigated after single oral administration of ¹⁴C-finasteride at a dose of 5 mg/1.85 MBq/kg to pregnant and lactating rats, respectively.
1. At 2 hr after single oral administration to 12-day and 18-day pregnant rats, the whole-body autoradiograms showed that the radioactivity in the fetus was lower than that in the maternal blood. In the fetal tissues, the radioactivity in adrenal gland and liver was similar to or higher than that in maternal blood. At 48 hr after dosing, the radioactivity was not detected in the fetus.
2. Following oral administration to 18-day pregnant rats, the radioactivity in the fetus was lower than that in the maternal plasma at 2 hr after dosing, and accounted for 0.11% of the administered dose. Although the radioactivity in the fetal liver at 2 hr after dosing was 1.5 times higher than that in the maternal plasma, the radioactivity in the other tissues was almost the same or lower. At 48 hr after the dose, the radioactivity in the fetal liver and kidney decreased to less than 1 % of the radioactivity at 2 hr after dosing, while the radioactivity was not detected in the other fetal tissues.
3. The radioactivity in the milk reached its peak (2.86 μg eq./ml) at 2 hr after single oral administration to lactating rats. From 2 to 24 hr, the radioactivity in the milk declined similarly to that in plasma with a terminal half-life of 3.8 hr. The ratios of radioactivity concentrations to those in plasma remained virtually unchanged for up to 8 hr after administration.

View full abstract

The absorption, distribution, metabolism and excretion of losartan were investigated in male and female rats after a single administration.
1. There were no sex-related differences in the pharmacokinetic parameters of radioactivity in plasma and blood of rats after oral (10 mg/kg) and intravenous dosing (3 mg/kg) of ¹⁴C-losartan.
2. Bioavailabilities after oral administration of losartan to male rats at doses of 15, 45 and 135 mg/kg were 31.5%, 35.5% and 38.2%, respectively.
3. After a single oral administration of ¹⁴C-losartan (10 mg/kg) to male rats, whole-body autoradiography showed that most of the radioactivity was rapidly and widely distributed, particularly to the gastrointestinal tract, liver and urine present in the bladder, and the radioactivity declined to very low levels within 48 hr. The quantitative tissue analysis showed that the highest levels of radioactivity were found in liver at 30 min after dosing, followed by stomach, small intestine, kidney and plasma. By 96 hr after administration, the radioactivity in the liver was less than 1 % of the level seen at 30 min after dosing, and the concentrations in the other tissues were below the detection limit of the assay.
4. After oral administration of ¹⁴C-losartan (10 mg/kg) to male rats, less than 3.5% of administered radioactivity was distributed to blood cells, and more than 99% of the radioactivity was bound to plasma proteins.
5. Within 3 hr after injection of ¹⁴C-losartan (10 mg/kg) to male rats, 19.8%, 32.1%, 89.6% and 51.4% of administered radioactivity were present in the stomach, duodenum, jejunum and ileum, respectively.
6. Within 48 hr after oral administration of ¹⁴C-losartan (10 mg/kg) to rats, 62.2% (male) and 59.5% (female) of administered radioactivity were excreted into bile. Within 168 hr after administration to male rats, 4.4% and 94% of administered radioactivity were excreted into urine and feces, respectively, and the enterohepatic circulation accounted for approximately 16% of administered bile within 8 hr after administration.
7. Losartan and its metabolites M-1, M-2, M-4 and M-5 were found in the liver and bile of male and female rats at 2 hr and 6 hr after oral administration of ¹⁴C-losartan (10 mg/kg). In the kidney of male rats, losartan, M-1, M-2 and M4 were found, while losartan, M-1 and M-4 were detected in the kidney of female rats. Within 24 hr after oral administration, the percentage of urinary excretion of losartan and M-11 was 0.3% and 1.3% in male rats, and 9.1% and 0.0% in female rats, respectively.

View full abstract

The absorption, distribution, metabolism and excretion of losartan were investigated in male rats after repeated oral administration. The effects on liver weight, protein concentration and drug metabolizing enzyme activities were also examined.
1. ¹⁴C-Losartan was administered to male rats at a dose of 10 mg/kg/day for 21 days. The plasma levels of radioactivity reached a steady state by 6th day, and the concentration at 72 hr after 21st dosing represented 10% of the corresponding C_max of 1.9 μg eq./ml.
2. Urinary or fecal excretion of radioactivity within 24 hr after each administration was similar. Within 72 hr after 21st dosing, approximately 2.1% and 94% of the total dose were excreted into urine and feces, respectively.
3. Tissue distribution of ¹⁴C-losartan in non-fasting male rats was studied after 1st, 7th, 14th and 21st oral administration at a dose of 10 mg/kg/day. At 8 hr after 1st dosing, quantitative tissue analysis indicated that the highest levels of radioactivity were found in the liver, followed by the large intestine, cecum and kidney. In the other tissues, the radioactivity levels were lower than that in plasma. In all tissues, the radioactivity at 24 hr after the dosing decreased to less than 32% of the levels observed at 8 hr or were below the limit of detection. The radioactivity reached nearly steady state in the kidney after 7th dosing and in the lung after 14th dosing. The radioactivity in plasma and tissues progressively decreased with time up to 96 hr after the last dosing. However, the radioactivity was eliminated very slowly from aorta.
4. A small amount of losartan was excreted in urine only after 6th dosing. The major metabolites in the urine were identified as M-10 and M-11. On the other hand, a large amount of losartan was excreted in feces, and M-1, M-2 and M-4 were also found. In liver and kidney samples at 8 hr after 1st and 21st dosing, losartan and M-4 were mainly found. No differences in urinary or fecal excretion of losartan and its metabolites were observed after 6th, 13th and 21st administration.
5. At 24 hr and 2 weeks after repeated oral administration of losartan for 7 days at a dose of 10 mg/kg/day, losartan had no effect on liver weight, microsomal protein concentration and drug metabolizing enzyme activities in liver microsomes. On the other hand, as compared with control, a slight, but statistically significant decrease in the amount of cytochrome b₅ and cytochrome P-450 was observed at 24 hr after repeated oral administration of losartan at a dose of 135 mg/kg/day, whereas no differences were observed at 2 weeks after repeated administration.

View full abstract

The transfer of losartan into the fetus and milk was investigated after single oral administration of ¹⁴C-losartan at a dose of 10 mg/kg to pregnant and lactating rats, respectively.
1. At 1, 8 and 24 hr after administration of ¹⁴C-losartan to 13-day pregnant rats, the whole-body autoradiography showed that no radioactivity was distributed to the fetus. Very low levels of radioactivity were detected in the fetus at 8 and 24 hr following administration to 18-day pregnant rats.
2. The maternal tissues of 18-day pregnant rats had the highest levels of radioactivity at 1 hr after administration and thereafter, the radioactivity declined with time, whereas the radioactivity in fetal tissues reached its peak between 1 and 8 hr after dosing and remained virtually unchanged from 8 to 24 hr. At 24 hr after administration, the radioactivity levels in the fetal blood, liver and kidney, and in the whole fetus were higher than that in the maternal plasma. At 8 or 24 hr after dosing, the radioactivity in the fetus accounted for 0.01% of the administered dose, indicating a slow transfer of the radioactivity into the fetal tissues.
3. Following oral administration of ¹⁴C-losartan to lactating rats on the 11th day after delivery, the radioactivity in the milk peaked at 8 hr after administration, indicating that the transfer of radioactivity into the milk is very slow. From 8 to 48 hr, the radioactivity in the milk declined similarly to that in plasma with a terminal t_1/2 of approximately 16 hr. At 48 hr after dosing, the radioactivity level in the milk corresponded to 45% of the plasma concentration.

View full abstract

Many chemicals manifest drug toxicity by direct interaction with cell components, but some chemicals cause severe toxicity by formations of active metabolites or reactive intermediates.
We showed that heterocyclic amines from protein pyrolysates and arylamines are oxidized to N-hydroxy-derivatives by CYP (cytochrome P450) 1A2. Moreover, these N-hydroxy-derivatives are further activated by esterification, such as O-acetylation and O-sulfation. We purified these enzymes from hamster and rat livers and cloned their cDNAs and expressed in COS-I cell to characterize their activities. Two different O-acetylating enzymes (AT-I and AT-II) exisit in hamster livers. AT-I is able to utilize both acetyl-CoA and arylhydroxamic acids as acetyl donors, in contrast, AT-II is able to utilize only acetyl-CoA. We found that in tissues of slow acetylators, the expression of AT-II, but not AT-I, is absent and the level of mRNA of AT-II is normal. Analysis of genomic DNA indicated that AT-II DNA from slow acetylators have a point mutation (C→T) to form premature stop codon (TGA). Moreover, we found that Salmonella strains of the Ames test have only AT-I type acetyltransferase and are lacking in AT-II type acetyltransferase and sulfotransferase. We created, therefore, new tester strain (SAT 138) by expression of hamster AT-I in TA 1945. SAT 138 showed markedly enhanced sensitivity towards N-hydroxyarylamine, arylhydroxamic acid and benzidine.

View full abstract

Recent studies of prediction for time courses of drug action are introduced. Anticonvulsive action of diazepam and positive inotropic action of ouabain are predicable by means of physiological pharmacokinetics combined with drug receptor binding behavior. Analgesic actions of indomethacin and ibuprofen in inflammation are more reliable and stable in the constant i.v. infusion than the bolus injection in rats. Onset of analgesic actions of pentazocin and eptazocin are sufficiently delayed from the concentration peaks and also from the binding maxima to opioid receptor in brain of rats. AUC of time course of analsic action is found for a reliable indicator.

View full abstract