Excretion Of Radioactivity Research Articles

Route-Dependent Comparative Metabolism of [ 14C]Toluene 2,4-Diisocyanate and [ 14C]Toluene 2,4-Diamine in Fischer 344 Rats

This study was initiated to evaluate the pharmacokinetics/metabolism of 14C-labeled toluene 2,4-diisocyanate (2,4-[ 14C]-TDI) following oral and inhalation exposure in the rat. For comparison, the pharmacokinetics/metabolism of toluene 2,4-diamine (2,4-[ 14C]TDA) was also evaluated. Groups of 3 or 4 male rats were given either a single 60 mg/kg oral dose of 2,4-[ 14C]-TDI or were exposed to 2,4-[ 14C]TDI vapors at a target concentration of 2 ppm for a 4-hr period. Additional groups of male rats were given single 3 or 60 mg/kg oral doses or a single 3 mg/kg intravenous (iv) dose of 2,4-[ 14C]TDA. All rats were euthanized by 48 hr postexposure. Following oral administration of 2,4-[ 14C]TDI, >93% of the administered radioactivity was recovered in the urine, feces, cage wash, and tissues. Approximately 8% of the oral dose was excreted in the urine while 81% was eliminated in the feces. It is estimated that during inhalation exposure, essentially all of the inhaled 2,4-[ 14C]TDI was retained by the animal. At 48 hr post-inhalation exposure approximately 15 and 47% of the recovered radioactivity was in the urine and feces, respectively. Following oral or inhalation exposure to 2,4-[ 14C]TDI, no radioactivity was eliminated as either expired 14C organics or 14CO 2. Comparison of the 2,4-[ 14C]TDI inhalation group with the oral 2,4-[ 14C]TDI and 2,4-[ 14C]TDA treatment groups indicated that a larger percentage of the inhaled radioactivity was in the tissues/carcass (34% vs 2-4%) and the excretion of radioactivity into the urine was slower ( t 1 2 20 hr vs 5-8 hr) following TDI inhalation. The total amount of free + acetylated TDA metabolites detected in the urine specimens (0-12 hr) following oral and inhalation exposure to 2,4-[ 14C]TDI was 15 and 0.26 μg eq 2,4-IDA, respectively. No free 2,4-IDA was detected in the urine specimen from the inhalation group. In comparison. 638 and 20 μg eq 2,4-IDA was detected in the urine specimen after oral administration of 60 and 3 mg/kg 2,4-[ 14C]TDA, respectively. Following 2,4-[ 14C]TDI inhalation and oral exposure approximately 90 and 65% of the quantitated urinary metabolites existed as acid-labile conjugates, respectively. In contrast, only 16-39% of the quantitated urinary metabolites existed as acid-labile conjugates following oral administration of 2.4-[ 14C]TDA. Inhalation exposure to 2,4-TDI primarily results in the formation of acid-labile conjugates with little or no 2,4-IDA being formed. This suggests that the metabolic disposition of inhaled 2,4-TDI is quite different than the disposition observed following orally administered 2,4-TDI or iv and orally administered 2,4-TDA. The route-dependent differences in 2,4-TDI disposition and metabolism may explain why TDI was not carcinogenic in rodents following inhalation exposure.

Distribution, kinetics and elimination of radioactivity after intravenous and intramuscular injection of 14C-savoxepine loaded poly( D, L-lactic acid) nanospheres to rats

Biodegradable poly( D, L-lactic acid) nanoparticles loaded with 14C-savoxepine were prepared using a salting-out process avoiding the use of chlorinated solvents and surfactants. Their sustained release properties after intravenous (i.v.) and intramuscular (i.m.) injection were assessed in rats. The pharmacokinetics, excretion and distribution of radioactive substances derived from 14C-savoxepine loaded in particles and as a free test compound in solution were determined by liquid scintillation counting. Particles with a mean diameter of 736 nm and 8.4% compound loading exhibited a sustained release over more than one week. 5.4 days after i.m. injection of the nanoparticles 50% of the initial radioactivity remained in the rats, mainly at the injection site. Stable plasma levels of 14C were observed over 7 days. After injection of the free compound in solution (i.v. or i.m.) 50% of the initial dose of radio-activity was eliminated in less than one day. After i.v. injection of the nanoparticles an effective sustained release was observed. However, the poly (vinyl alcohol) coating of these nanoparticles could not prevent a massive uptake by the reticuloendothelial system.

Growth characteristics of rats receiving ractopamine hydrochloride and the metabolic disposition of ractopamine hydrochloride after oral or intraperitoneal administration.

Objectives of this study were 1) to measure the effect of oral or i.p. administration of ractopamine HCl on growth and feed utilization in rats, 2) to determine the total absorption of [14C]ractopamine HCl after oral administration, and 3) to determine the disposition of radioactivity and the urinary elimination of unchanged [14C]ractopamine in rats after oral or i.p. administration of [14C]ractopamine. Twenty-seven female Sprague-Dawley rats (164.6 +/- 5.7 g) were randomly assigned to control (CONT), oral (ORAL), and i.p. (IP) treatments. Control and ORAL rats were implanted i.p with sham pumps, and IP rats were implanted i.p. with osmotic pumps primed to deliver 312 micrograms of ractopamine HCl per 24 h. Control and IP rats received no dietary ractopamine, but ORAL rats received 20 mg of ractopamine HCl/kg of diet. The IP rats had greater cumulative net weight gains and ADG on d 2, 6, 8, 10, and 12 than CONT rats. The ADFI was greater for ORAL rats on d 2 and 4 than for CONT rats, and the gain:feed ratio was greater on d 2, 6, 8, 10, and 12 for IP rats than for CONT rats. Net weight gain, ADG, and gain:feed ratio did not differ between ORAL and CONT rats. Absorption of radioactivity administered orally as [14C]ractopamine (2.9 mg) was 87.9% during a 24-h experimental period; biliary, urinary, and fecal excretion of radioactivity was 58.5%, 28.7%, and 1.4% of that administered, respectively. Urine from rats dosed orally with [14C]ractopamine contained 1.9% of the radioactivity as the parent compound, and urine from rats dosed i.p. contained 22.6% of the radioactivity as parent ractopamine. Ractopamine HCl increased weight gain and efficiency of feed utilization when administered i.p. to rats, but not when administered orally. The ineffectiveness of oral ractopamine for stimulating the growth of rats was probably due to extensive presystemic metabolism of ractopamine.

Percutaneous Absorption of Azone following Single and Multiple Doses to Human Volunteers

Azone (1-dodecylazacycloheptan-2-one) is an agent that has been shown to enhance percutaneous absorption of drugs. Azone is thought to act by partitioning into skin lipid bilayers and thereby disrupting the structure. An open-label study was done with nine volunteers (two males, seven females; aged 51-76 years) in which Azone cream (1.6%; 100 mg) was topically dosed on a 5 x 10-cm area of the ventral forearm for 21 consecutive days. On days 1, 8, and 15, the Azone cream contained 47 microCi of [14C]Azone. The skin application site was washed with soap and water after each 24-h dosing. Percutaneous absorption was determined by urinary radioactivity excretion. The [14C]Azone was ring labeled [14C-2-cyclo-heptan]. Radiochemical purity was > 98.6% and cold Azone purity was 99%. Percutaneous absorption of the first dose (day 1) was 1.84 +/- 1.56% (SD) of applied dose for 24-h skin application time. Day 8 percutaneous absorption, after repeated application, increased significantly (p < 0.002) to 2.76 +/- 1.91%. Day 15 percutaneous absorption, after continued repeated application, stayed the same at 2.72 +/- 1.21%. In humans, repeated application of Azone results in an initial self-absorption enhancement, probably due to its mechanism of action. However, steady-state percutaneous absorption of Azone is established after this initial change. Thus, Azone can enhance its own absorption as well as that of other compounds. This should be considered relevant for any pharmacological or toxicological evaluation. Washing the skin site of application with soap and water only recovered 1-2% of applied radioactivity. Previous published studies recovered the Azone dose with ethanol washes. Thus, there could potentially be an accumulation of Azone in skin.

Pharmacokinetic Studies of New 5-FU Derivative, BOF-A2. (1): Absorption, Distribution, Metabolism and Excretion after Single and Repeated Oral Administration to Rats.

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 Cmax 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 Cmax. 4. After a single administration to male and female rats, the ratio of the AUC0-24 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.

Metabolic Fate of a Benzoylphenylurea Derivative, HO-221. (I). Absorption, Distribution and Excretion in Rats after Single Administration.

The absorption, distribution and excretion of a benzoylphenylurea derivative, HO-221 were studied in rats after single oral administration of 14C(Pc)-HO-221 or 14C(Pn)-HO-221. 1. The radioactivity level in the blood reached a maximum at 12 hr after administration of 14C(Pc)-HO-221 to male and female rats at a dose of 25 mg/kg. The absorption ratio was about 9 % as caluculated from the mass balance study. The Cm and AUC were not dose-related at the dose range of 8.3 to 25 mg/kg. The absorption from the digestive tracts tended to decrease by fasting. The Cmax and AUC derived from 14C(Pn)-HO-221 were both 2 times higher than those derived from 14C(Pc)-HO-221. 2. The radioactivity levels in the fat, liver, brown fat, adrenal gland and Harderian gland were high after administration of 14C(Pc)-HO-221 to male and female rats. The radioactivity in the tissues was eliminated rapidly, except the kidney and liver. 3. The excretion of radioactivity in the urine and feces was about 2 and 95% of the dose, respectively, within 120 hr after administration of 14C (Pc)-HO-221 to male and female rats. The excretion of radioactivity in the bile was about 5% of the dose. About 30% of the biliary excreta (1% of the dose) was re-absorbed. The excretion of radioactivity in the urine was 3 % of the dose within 120 hr after administration of 14C(Pn)-HO 221. 4. The protein binding ratios in vitro and vivo were more than 99% but the binding was reversible.

Metabolic Fate of YM175. Distribution and Excretion of Radioactivity after Intravenous Administration of 14C-YM175 to Rats.

ラットに14C-YM175を0.3mg/kg静脈内投与した時の分布および排泄について検討し，以下の結果を得た． 1．14C-YM175はラットに静脈内投与後，標的組織である骨に速やかにかつ高濃度に移行し，長期間そこに留まった．その他の組織では，排泄器官である腎臓が投与後5分で骨に匹敵する濃度を示したが，その他の組織における放射能濃度は血漿中濃度よりも低く，特に脳内濃度は低かった．放射能の消失は脾臓，肝臓，骨髄，肋骨および上腕骨で緩やかであったが，その他の組織では比較的速やかであった． 2．上腕骨および肋骨内放射能濃度は2相性の低下を示した．t1/2αはそれぞれ4.8および8.9日，t1/2βはそれぞれ331および214日であった． 3．上腕骨オートラジオグラムにおいて，骨幹端に最も高い放射能が認められた．次いで骨端および骨幹の放射能が高く，骨髄腔への分布はほとんど認められなかった．上腕骨内の放射能は最初に取り込まれた部位に留まり，成長に伴い伸長した部位には認められなかった．上腕骨内放射能濃度は脱灰により，脱灰前値の0.2～0.6%に低下した． 4．投与後168時間までの尿および糞中放射能排泄率は投与量のそれぞれ64.5および2.5%であった，投与後168時間の体内放射能残存率は投与量の32.9%であり，これらを合計した総回収率は99.9%であった．胆管カニューレを施したラットに静脈内投与後48時間の胆汁および尿中放射能排泄率は投与量のそれぞれ0.8および57.0%であった．

Metabolic Fate of a Benzoylphenylurea Derivative, HO-221. (IV). Absorption, Metabolism and Excretion in Dogs.

The absorption, metabolism and excretion of benzoylphenylurea derivative, HO-221 in male dogs were studied after oral administration of 14C(Pc)-HO-221 at a dose of 25 mg/kg. 1. The radioactivity levels in the plasma reached a maximum at 24 hr after administration and declined with a half-life of 220 hr up to 120 hr. 2. The excretion of radioactivity in the urine and feces was 0.2 and 98.2% of the dose, respectively, within 120 hr after administration. The excretion of radioactivity in the bile was 0.5% of the dose within 48 hr after administration. 3. The protein binding ratios in vitro and vivo were more than 99% both in the case of dog or human plasma, but binding was reversible. 4. The parent compound was a major component in the plasma. M5 and M6 were also observed. Polar metabolites in origin accounted for about 80% of the radioactivity in the urine. The parent compound was a major component in the feces and M5 was detected as a minor metabolite. Polar metabolites in origin were major in the bile, part of which were conjugates.

Studies on the Metabolic Fate of Loprinone Hydrochloride. (2): Transfer into Fetus and Milk.

Transfer of radioactivity into the fetus and milk after a single intravenous administration of 14C-Loprinone hydrochloride to pregnant or lactating rats were investigated. 1. On day 12 and 19 of gestation, the tissue levels of radioactivity in the fetus at 5 min after dosing were lower than the plasma levels of radioactivity in the maternal rat. But the elimination of radioactivity in the fetus was slower than that in the maternal plasma. 2. In the fetus on day 19 of gestation, the levels of radioactivity in the kidney, liver and gut were higher than those in the other tissues. 3. The elimination of radioactivity from maternal tissues except liver, kidney, uterus and placenta, was rapid. But 24 hr after dosing, the levels of radioactivity in all tissues were very low. 4. In the fetus on day 12 and 19 of gestation, almost all of radioactivity corresponded to the unchanged form. 5. The milk-to-plasma co ncentration ratio reached the maximum value of 97.1 at 4 hr after dosing. The disappearance of the radioactivity from the milk was slower than that from the maternal plasma. And small amount of radioactivity was detected in the milk at 48 hr after dosing. 6. The radioactivity in the milk consisted mainly from the unchanged form.

Metabolic Fate of Human Urinary Kallidinogenase(SK-827) (2): Distribution, Accumulation and Urinary or Biliary Excretion in Rats after Single or Repeated Intravenous Administration.

The distribution, accumulation and urinary or biliary excretion of SK-827 were investigated in male rats after single or repeated intravenous administrations of 125I-SK-827. 1. The blood trichloroacetic acid insoluble (TCA-insoluble) radioactivity after a single intravenous injection of 125I-SK-827 at a dose of 5×10-3 PNAU (p-nitroaniline unit) /kg decreased rapidly within 1 hr, but thereafter in more gradual rate. At 5 min ?? 1 hr after injection, the TCA-insoluble radioactivity in the liver, adrenal, spleen, kidney and bone marrow were higher than that in the blood. At 5 min after injection, more than 90% of administered radioactivity was concentrated in the liver. The TCA-insoluble radioactivity in these tissues decreased rapidly within 1 hr, and the elimination was similar to that in the blood thereafter. Distribution profiles of radioactivity after a single constant rate intravenous infusion did not differ from those after intravenous injection. 2. TCA-insoluble radioactivity in the liver, kidney and spleen at 1, 3 and 24 hr after 4-day repeated intravenous injections of 125I-SK-827 at the dose of 5×10-3 PNAU/kg were 2 ?? 10 times higher than those observed after a single dose but the TCA-insoluble radioactivity in these tissues were almost constant from 4-day to 7-day repeated dosing. 3. Within 24 hr after a single intravenous injection of 125I-SK-827 at a dose of 5×10-3 PNAU/kg, more than 90% of administered radioactivity was excreted into urine. However, urinary excretion of TCA-insoluble radioactivity was only 1% of administered dose within 3 hr after injection. 4. Within 48 hr after a single intravenous injection of 125I-SK-827 at a dose of 5×10-3 PNAU/kg, about 20% of administered radioactivity was excreted into bile. However, biliary excretion of TCA-insoluble radioactivity was only 3% of administered dose within 3 hr after injection.

Metabolic Fate of a Benzoylphenylurea Derivative, Ho-221. (III). Transfer into Fetus, Milk and Tumor.

The transfer into fetus, milk and tumor of a benzoylphenylurea derivative, HO-221 was studied after oral administration of 14C(Pc) HO-221 to rats at a dose of 25 mg/kg. The radioactivity levels in the fetuses on the 12th and 18th days of gestation were 35 and 67% of those in the maternal plasma, respectively. The radioactivity level in the fetus on the 12th day of gestation was below the detection limit at 48 hr after administration. The radioactivity levels in the fetal tissues, except the intestinal contents, on the 18th day of gestation were less than 14% of the maximum. The radioactivity level in the milk was 3-4 times higher than that in the plasma up to 12 hr after administration. The elimination of radioactivity from the milk was more rapid than from the plasma. The radioactivity level in the tumor was similar to that in the plasma. No difference was noted in the distribution of radioactivity into the tissues and the excretion of radioactivity in the urine and feces between tumor bearing and normal male rats.

Metabolic Fate of a Benzoylphenylurea Derivative, HO-221. (II). Repeated Dosing Study and Metabolism in Rats.

The absorption, distribution and excretion of a benzoylphenylurea derivative, HO-221 were studied after repeated administration of 14C(Pc)-HO-221 once a day for a maximum of 28 days to male rats at a dose of 25 mg/kg. The radioactivity levels in the blood at 24 hr after daily dosing reached a steady state after the 20th dosing, being 2 times higher than after the 7th dosing. The radioactivity levels in all the tissues after the 28th dosing were less than 2 times of those after single dosing. The radioactivity was still detected at 240 hr after administration but only in the kidney and liver. The excretion of radioactivity in the urine and feces 24 hr after daily dosing did not change after the 4th dosing, and after the final repeated dosing was similar to that after single dosing. The metabolism was investigated after administration of 14C(Pc)-HO-221 or 14C(Pn)-HO-221 to male rats. The parent compound accounted for about 70% of the radioactivity in the plasma at 6 hr after administration. M5, M6, M7 and ο-nitrobenzamide were also detected in the plasma. The parent compound and M5 were principally observed in the liver, kid ney and fat. The conjugate of M6 was major metabolite in the urine, accounting for about 46% of the radioactivity in the urine. Unknown metabolites were major components in the bile. The parent compound and M5 were major in the feces. No difference was noted in urinary and fecal metabolites between the single and repeated dosing groups. UDPG transferase activity increased significantly by repeated dosing of HO-221.

Pharmacokinetics of a New Benzimidazole Sulfoxide Derivative, E3810. (2): Absorption, Distribution, Metabolism and Excretion in Rats.

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.

Metabolic Fate of YM060. (1): Plasma Concentration, Distribution and Excretion after Intravenous Administration of 14C-YM060 to Rats.

The plasma concentration, tissue distribution and excretion of radioactivity were investigated after a single intravenous administration of 1 mg/kg of 14C-YM060 to rats. 1. Whole blood radioactivity decreased bi-phasically with terminal elimination half life (t1/2) of 78.0 min. Plasma radioactivity showed steady levels up to 15 min after dosing, then decreased with a t1/2 of 79.8 min. Plasma unchanged drug concentrations decreased bi-phasically with a t1/2 of 36.6 min. AUC0-∞ values for whole blood radioactivity, plasma radioactivity and unchanged drug were 398.7 ng equiv. ·h/ml, 412.6 ng equiv. ·h/ml and 123.6 ng·h/ml, respectively. 2. Radioactivity distributed quickly into various tissues, showing a peak concentration at 5 min after dosing in most tissues. Radioactivity levels were highest in the kidney, followed by the lung, liver, adrenal, pancreas, hypophysis, submandibular gland, stomach and small intestine, and were lowest in the brain. Radioactivity disappeared rapidly from tissues, and the levels in most tissues at 24 hr after dosing were less than 1.2% of the peak concentrations. 3. Within 72 hr after dosing, 29.7% and 70.9% of the dosed radioactivity was excreted in the urine and feces, respectively. In bile-duct cannulated rats, 67.2% and 31.1% of the dosed radioactivity was excreted within 72 hr in the bile and urine, respectively. Of the radioactivity excreted in the bile, 33.5% was reabsorbed.

Metabolic Fate of (.+-.)-2-((2-(isobutylmethylamino)benzyl)sulfinyl)-1H-benzimidazole (NC-1300-O-3). (2): Absorption, Distribution and Excretion after Consecutive Oral Administration, and Transfer into Fetus and Milk in Rats.

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.

Metabolism of 1,1-dichloro-2,2,2-trifluoroethane in rats.

1. Chlorofluorohydrocarbons are presently being developed as alternatives for ozone-depleting chlorofluorocarbons. 1,1-Dichloro-2,2,2-trifluoro-[2-14C]-ethane (HCFC-123) is a chlorofluorohydrocarbon with potential widespread use and associated human exposure. As a part of the toxicological evaluation of HCFC-123, its metabolism was studied in rodents in a closed recirculating exposure system. 2. Two male rats were individually exposed for 6 h. Excretion of radioactivity was monitored for 48 h after the start of the exposure. Of the radioactivity introduced into the chamber, 14% was recovered in urine within the period of observation. Excretion of metabolites in the urine was very slow. 3. Trifluoroacetic acid was the major metabolite of HCFC-123 and N-trifluoroacetyl-2-aminoethanol and N-acetyl-S-(2,2-dichloro-1,1-difluoroethyl)-L-cysteine were identified as minor urinary metabolites of HCFC-123. 4. Forty-eight hours after the start of the exposure, covalent binding of radioactive metabolites to protein was highest in liver followed by kidney and lung. Covalent binding above background levels was not observed in pancreas and testis, the target organs of HCFC-123 tumourigenicity. 5. These results suggest that the biotransformation of HCFC-123 in rodents follows a pathway identical to those of the extensively studied structural analogue halothane.

Absorption, Distribution, Excretion and Effects on Drug Metabolizing Enzyme Activities of a New Antiplatelet Drug, Ethyl 2-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)pyrrol-1-ylacetate(KBT-3022), after Multiple Oral Administration in Mice.

Absorption, distribution, excretion, enzyme induction and effect to platelet were investigated in male mice after oral administration of an antiplatelet drug, KBT-3022. 1. Radioactivity levels in the plasma 24 hr after daily oral administration of 14C-KBT-3022 reached a steady state by the 4th dosing. The radioactivity levels after the 21st dosing showed a broad peak with about half of the Cmax after single dosing but had a similar AUC0-24 h.2. Radioactivity levels in tissues 24 hr after daily oral administration of 14CKBT-3022 increased with the number of doses and reached a steady state by the 21st dosing except the spleen. The radioactivity levels in the lung, heart and testis after the 21st dosing were 5-6 times higher than those after single dosing, but those in the other tissues were lower than 4 times. Elimination of radioactivity from tissues after the 21st dosing was slower than that after single dosing. At 72 hr after the 21st dosing, the radioactivity level in the aorta was 50% of the maximum and those in the skin, testis, lung, fat and spleen were 24-35% of the maximum. High level of radioactivity was noted in the deferent duct as revealed by whole body autoradiography. 3. No marked difference was observed in plasma concentration of 6-keto-PGF1α and serum concentration of TXB2 between the single and repeated dosing groups, although the accumulation of radioactivity was noted in the aorta after multiple doses of 14C-KBT-3022. From these results, metabolites in the aorta would not inhibit the production of PGI2. 4. Excretion of radioactivity in the urine and feces did not change with the number of doses and was 1.3 and 92.7% of the cumulative dose, respectively, within 120 hr after the 21st dosing. 5. No significant effect on hepatic drug-metabolizing enzyme system was observed after repeated dosing of KBT-3022.

Plasma Concentration, Distribution and Excretion of 14C-Milrinone in Rats following Single and Repeated Intravenous Administration.

Plasma concentration, distribution and excretion of radioactivity were investigated after a single and repeated intravenous administration of 5 mg/kg of 14C-milrinone to male rats. 1. After a single dosing, the plasma concentrations declined bi-phasically with the elimination half life (t1/2) of 3.5 hr; the area under the plasma concentration-time curve (AUC), volume of distribution (Vdss) and total clearance (CLtotal) were 7.19 μg equiv. of milrinone·hr/ml, 873 ml/kg and 11.6 ml/min/kg, respectively. Plasma concentration-time curve of unchaged drug was similar to that of radioactivity. The AUC, t1/2, Vdss and CLtotal for unchaged drug were 3.2 hr, 7.35 μg·hr/ml, 727 ml/kg and 11.3 ml/min/kg, respectively. 2. Radioactivity was distributed rapidly to various tissues, showing peak levels 15 min after a single administration. At 15 min, levels of radioactivity in the kidney was approximately 4 times higer than that in the plasma, while concentrations in other tissues were similar to or lower than plasma concentrations. Radioactivity disappeared rapidly from most tissues, except the skin. After repeated administration of 14C-milrinone for 7 days, no radioactivity was accumulated in any tissues measured however, disappearance from the skin was relative ly slow. On the whole body autoradiogram 24 hr after repeated dosing, revealed that radioactivity was not observed in skin but was seen in the hair. At 72 hr, radioactivity was detected in the hair only, but the level was low. 3. Within 168 hr after a single dosing, 79.2% and 21.9% of dosed radioactivity were excreted in urine and feces, respectively, and 101.1% of the dose was recovered by both routes. After repeated dosing with 14C-milrinone for 7 days, cumulative excretion rates of radioactivity in urine and feces were 74.9% and 21.4%, being similar to those after a single dosing. Within 48 hr after administration of 14C-milrinone to bile duct-cannulated rats, 65.1%, 10.4% and 18.9% of dosed radioactivity were excreted in the urine, feces and bile, respectively, indicating that renal excretion was the main excretion route of milrinone.

Pharmacokinetic Studies of L-DOPS (L-threo-3,4-Dihydroxyphenylserine) in Renal Failure Rats.

14C標識したL-DOPSを用い，腎障害ラットにおけるL-DOPSの体内動態について検討を行なった． 14C-L-DOPS(10mg/kg)を経口投与した部分(5/6)腎摘出ラットの血清中14C濃度は，擬i手術群に比べT1/2が遅延し，Cmaxは3倍，AUC0-48は10倍に増加したが，尿，糞中14C排泄率(0-72hr)に差は認められなかった． 腎摘出ラットにおける血清中代謝物としては3-OM-DOPS，Vanillic acid(VA)，Protocatechuic acid(PA)およびVA，PAの抱合体が検出され，主要代謝物はVA，PAの抱合体であった． 主要組織における14C濃度は正常ラットと同様血清中濃度とパラレルに変化し腎摘出によっても特異的に14C濃度が増加する組織はなく，また組織からの消失は速やかで高い残留性を示す組織はなかった． 14C-L-DOPS(10mg/kg)を連続(1日1回7日間)投与した部分腎摘出ラットにおける初回，4回，7回投与後の血清中14C濃度推移は初回投与時と顕著な変化はなかった． 7日間連続投与後の組織中14C濃度は，単回投与時と比較し最高時点が早くなり組織からの消失は遅くなったが投与後72時間における濃度はすべて1.0μg eq./g以下となり残留性を示す組織は認められなかった．

Metabolic Fate of Quinapril Hydrochloride (I). Absorption, Distribution, Metabolism and Excretion of 14C-Quinapril Hydrochloride in Rats.

The metabolism and disposition of 14C-quinapril hydrochloride were studied in rats. The compound was mainly absorbed from the small intestine. The extent of absorption was estimated to be between 50 and 65% after an oral dose of 3 mg/ kg in fasting male rats. The plasma level of radioactivity reached a maximum at 0.5 hour, and the terminal half-life was 29.6 hours. Peak levels in plasma (Cmax) and the areas under the plasma concentration-time curve (AUC) were proportional to the dose between 1 and 30 mg/kg. In non-fasting condition Cmax decreased, but AUC did not alter. No sex-related differences were observed in pharmacokinetic parameters. High levels of radioactivity were observed in the liver, plasma, kidney, blood and the lung at 0.5 hour after the administration and the levels rapidly decreased in all tissues studied. Radioactivity was slightly detected only in the lung, liver and the kidney at 72 hours after the administration. Similar distribution characteristics were observed with the whole body autoradiograms. Residual radioactivity accounted for 0.1% in the carcasses at 120 hours after the administration. Binding extent of radioactivity to plasma proteins was between 95 and 97%. Radioactivity in plasma was hardly transferred to the blood cells. Quinaprilat, an active metabolite, was mainly detected in the plasma, urine, feces and the bile, but quinapril and other metabolites were hardly detected. Within 120 hours after oral administration of 14C-quinapril hydrochloride at a dose of 3 mg/kg to male rats, the urinary and fecal excretion of radioactivity were 18.8 and 78.6%, respectively. The excretion of radioactivity in female rats was similar to that in male rats. Within 48 hours after oral administration to bile-duct cannulated male rats, biliary excretion was 43%. Twenty two percents of radioactivity excreted in the bile was reabsorbed from the intestine.