Radioactivity In Urine Research Articles

Pharmacokinetic Studies of 3-Methyl-1-phenyl-2-pyrazolin-5-one(MCI-186): Metabolism in Rats, Dogs and Human.

In order to clalify the species difference in metabolism of MCI-186, the identification of metabolites, urinary excretion rates of unchanged MCI-186 and its metabolites, and in vitro metabolism were investigated in rats, dogs and human. 1. Main metabolites of MCI-186 were sulfate and glucuronide of MCI-186 in all species. In the urine of rats and dogs, excretion rates of sulfate were higher than those of glucuronide, however in the urine of human, excretion rate of glucuronide was higher than that of sulfate, therefore species difference was observed in urinary excretion. 2. Urinary excretion was the main excretion route in all species. Excretion rates of the unchanged MCI-186 to urine were less than 3 % of dose. In dogs and human, urinary excretion can be mostly explained by excretion of unchanged MCI-186, and its sulfate and glucuronide. However in rats, unknown metabolites were present at higher rates of 20 ?? 27% of the urinary radioactivities. And sex difference in urinary excretion was not observed mostly in rats. 3. Activities of formation of MCI-186 sulfate were higher than those of MCI-186 glucuronide at in vitro metabolism of MCI-186 with liver S9 of rats and dogs. And both activities were higher in male rats than in female rats.

Innocuity of agents for radiocontrast enhancement of urinary tract stones

Mineral kidney stones are frequently difficult to detect due to their radiotranslucency. We have recently developed a method that enhances the visibility of such stones by retrograde infusions of certain heavy metal salt solutions such as cesium or lanthanide gadolinium. This report describes toxicologic studies carried out on the use of those contrast agents to introduce this technique eventually into clinical trials. Systemic absorption was assessed in dogs through infusion of radioactive contrast agent into the renal pelvis with or without ureteral obstruction. Radioactivity in urine and blood was monitored. Local toxicity was studied in animals infused with the contrast agent at intervals up to 4 weeks. Reabsorption studies under high intrapelvic pressures (70 cm H2O or higher), demonstrated reabsorption of cesium. However, at normal intrapelvic pressures, only a moderate reabsorption of cesium was observed. No gadolinium reabsorption was detected even at high intrapelvic pressures. Histopathologic studies showed no major urothelial lesions but only a transient inflammatory reaction that was undetectable 4 weeks following exposure to gadolinium salts. Gadolinium salt solutions are good positive radiocontrast agents for mineral kidney stones without having serious toxic effects or systemic reabsorption.

In vivo stability, disposition and metabolism of a “hybrid” oligonucleotide phosphorothioate in rats

Oligodeoxynucleotide phosphorothioates containing segments of 2′- O-methyloligoribo-nucleotide phosphorothioates at both 3′- and 5′-ends (hybrid oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 ± 3.21% (mean ± SD) of the administered dose excreted within 24 hr and 38.13 ± 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 ± 0.13% of the administered dose excreted over 24 hr and 6.74 ± 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined oligodeoxynucleotide phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo, which may be important in the development of antisense oligonucleotides as therapeutic agents.

Absorption, tissue distribution and in vivo stability in rats of a hybrid antisense oligonucleotide following oral administration

In vivo stability and oral bioavailability of an oligodeoxynucleotide phosphorothioate containing segments of 2′- O-methyloligoribonucleotide phosphorothioates at both the 3′- and 5′-ends (hybrid oligonucleotide) were studied. A 25-mer 35S-labeled hybrid oligonucleotide was administered to rats by gavage at a dose of 50 mg/kg body weight. HPLC analysis revealed that this hybrid oligonucleotide was stable in the gastrointestinal tract for up to 6 hr following oral administration. Radioactivity associated with the hybrid oligonucleotide was detectable in portal venous plasma, systemic plasma, various tissues, and urine. Intact hybrid oligonucleotide was detected, by HPLC analysis, in portal venous plasma, systemic plasma, and various tissues. The majority of the radioactivity in urine was associated with degradative products with lower molecular weights, but the intact form was also detected. In summary, the hybrid oligonucleotide was absorbed intact through the gastrointestinal tract, indicating the possibility of oral administration of oligonucleotides, a finding that may be important in the development of antisense oligonucleotides as therapeutic agents.

Metabolism is an important route of pentamidine elimination in the rat: disposition of 14C-pentamidine and identification of metabolites in urine using liquid chromatography-tandem mass spectrometry.

This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of 14C-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22 +/- 2% (mean +/- S.D.) and 25 +/- 4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21 +/- 5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76 +/- 15% (mean +/- S.D.) of the total excreted radioactivity on day 1 and 97 +/- 1% on day 6. HPLC--tandem mass spectometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.

Dynamics of Streptococcus Histone Retention by Mouse Kidneys

To study the interaction of streptococcal histone-like protein with renal tissue, 2 groups of 12 mice were injected intravenously with either radioiodinated histone or bovine serum albumin. At intervals over 48 hr, 2 mice from each group were anesthetized and perfused with tissue culture medium and the amounts of radioactivity were measured in blood, urine, and kidneys. The streptococcal protein rapidly disappeared from the blood and accumulated in renal tissue. Kidney radioactivity was maximal at 2 hr and then declined steadily over the ensuing 46 hr. Retention of streptococcal protein in renal tissue was 2 orders higher than that of BSA throughout the experiment. Immunofluorescence staining of kidney sections showed that the histone protein was adsorbed to the basement membranes of the glomeruli and collecting tubules. There were similar rates of excretion of radioactivity in urine by the two groups of mice. Injection of preformed complexes of streptococcal histone and rabbit antibodies into a third group of mice resulted in deposits of immune complexes in glomeruli but did not change the overall rate at which the radiolabeled streptococcal protein was distributed. The accumulation of streptococcal histone in renal tissue, independently of antibodies or while contained in circulating immune complexes, makes it a potential virulence factor in the pathogenesis of poststreptococcal glomerulonephritis. Its pathogenic properties remain to be studied in an appropriate animal model.

In vivo stability and disposition of a self-stabilized oligodeoxynucleotide phosphorothioate in rats

The use of antisense oligonucleotides represents a novel, genetically based therapy. The biostability and pharmacokinetics of a 33-mer self-stabilized oligodeoxynucleotide with significant anti-HIV activity was determined in rats after intravenous administration of [35S]oligodeoxynucleotide. Plasma disappearance of the labeled oligodeoxynucleotide could be described by a two-compartment model, with half-lives of 0.54 and 41.44 h. The oligodeoxynucleotide in plasma remained mainly intact. Urinary excretion represented the major elimination pathway, with approximately 27% of the administered dose excreted within 24 h and 57% over 240 h. The majority of radioactivity in urine was attached to degradative products. Fecal excretion was a minor elimination pathway. A wide tissue distribution of the oligonucleotide was observed, with the majority of radioactivity in most tissues being intact. Compared with other linear oligonucleotide phosphorothioates, the self-stabilized oligonucleotide was more stable in vivo, which may be important in development of antisense oligonucleotides as therapeutic agents.

Significant Effects of Application Site and Occlusion on the Pharmacokinetics of Cutaneous Penetration and Biotransformation of Parathion in Vivo in Swine

Increasing attention has been paid to the variables of application site and dosing method in quantitation of chemical percutaneous absorption. Following topical and intravenous application of [ring‐U‐14C]parathion (PA) in weanling pigs, we have determined, in a previous publication, the profiles of14C and HPLC‐separated paraoxon (PO),p‐nitrophenol (PNP), andp‐nitrophenyl β‐D‐glucuronide (PNP‐G) in plasma, urine, tissues, and dosing device. The purpose of the present paper was to analyze these data further, focusing on a quantitation of the effects of application site (back versus abdomen) and dosing method (occluded versus nonoccluded) onin vivodisposition of both the parent PA and its sequential metabolites PO, PNP, and PNP‐G. Cutaneous and systemic disposition parameters were determined using a numerical simulation modeling approach and moments analysis. Mean systemic bioavailability values of 8.9–9.2% for abdomen and 14.7–19.7% for back were determined. Under different dosing conditions, 1–35% of the topical dose was metabolized dermally, and 9–19% systemically. Radioactivity in plasma and urine was predominantly contributed by PNP‐G and PNP. Site differences in14C percutaneous absorption were governed by the differences in transport of PA, PO, and PNP from epidermis into blood, by local tissue distribution, and by the cutaneous metabolism to PNP. Systemic bioavailability of PA was higher from the back than from the abdomen. Occlusion not only increased the amount of14C absorption and shortened the mean residence time in most compartments but also altered the systemic versus cutaneous biotransformation pattern. The occlusion effect of enhancing PA cutaneous metabolism appears to be the most important mechanism for the previously observed increased14C absorption. Significant site–occlusion interactions were demonstrated, indicating that one cannot describe site differences without referring to the specific dosing method and method andvice versa.Moreover, novel and practical computational methods (bioavailability–excretion analysis, bioavailability–bioavailability analysis) to clarifyin vivocutaneous metabolism from the systemic biotransformation of topically applied compounds were developed.

Pharmacokinetics and tissue distribution in rats of an oligodeoxynucleotide phosphorothioate (GEM 91) developed as a therapeutic agent for human immunodeficiency virus type-1

An antisense oligodeoxynucleotide phosphorothioate, namely gene expression modulator 91 (GEM 91), has been demonstrated to have significant anti-human immunodeficiency virus activity in various tissue culture models. The present study was undertaken to determine the pharmacokinetics and tissue distribution of GEM 91 in rats following i.v. bolus administration of 35S-radiolabeled GEM 91. Plasma disappearance curves for GEM 91-derived radioactivity could be described by the sum of two exponentials, with half-lives (mean ± SEM) of 0.95 (± 0.07) and 47.57 (± 14.48) hr. Urinary excretion represented the major pathway of elimination of GEM 91, with 26.67 ± 6.46% (mean ± SD) of the administered dose excreted within 24 hr and 58.12 ± 4.36% over 240 hr after GEM 91 administration. Fecal excretion was a minor pathway of elimination of GEM 91 with 1.4 ± 0.62% (mean ± SD) of the administered dose excreted over 24 hr and 8.54 ± 0.64% over 240 hr. A wide tissue distribution of GEM 91 was observed. During the initial 30 min, the highest levels of tissue radioactivity were found in the kidney, liver, spleen, lungs, and heart. Radioactivity was retained over longer time periods in the kidneys, liver, heart, and intestine. Analyses of the extracted radioactivities from plasma, kidney, and liver by gel electrophoresis showed the presence of both intact GEM 91 and degradative products with smaller molecular weights. Radioactivity in urine was found to be degradative metabolites of GEM 91. Based on the experimental data, pharmacokinetic parameters for GEM 91 in each tissue and biological fluids were calculated using computer-based two-compartmental i.v. bolus or absorption models. This study is important not only in providing the basis for future studies of GEM 91 in humans, but also in understanding the pharmacology and toxicology of antisense oligodeoxynucleotide phosphorothioates, in general.

Toxicokinetics of 4-methylimidazole in the male F344 rat.

The toxicokinetics and metabolism of 4-methylimidazole (4-MZ) have been studied in the male F344 rat using 14C radiolabelled compound. Radioactivity in plasma and urine was profiled by hplc. After gavage administration of 50 mg/kg, about 85% of the administered radioactivity was recovered in urine within 48 h. The majority of the radioactivity in urine or plasma was associated with the parent compound and only one minor hydrophilic metabolite was present in urine and in plasma. Elimination of radioactivity via fecal, biliary or respiration was negligible. Elimination of 4-MZ after an i.v. dose of 5 mg/kg can be described by a two-compartment process with an estimated half-life of 1.8 h and an estimated apparent volume of distribution of 2.3 litre/kg. After gavage at doses of 5, 50 and 150 mg/kg, 4-MZ was readily absorbed with a estimated bioavailability of 60-70%. Urinary excretion data indicated that renal clearance of 4-MZ accounted for about 80% of total body plasma clearance. Based on the estimated AUC of metabolite and the estimated renal clearance of 4-MZ, the formation of metabolite and the renal clearance of 4-MZ appeared to be a saturable process.

Disposition of KW-4679. (1). Absorption, Distribution and Excretion of 14C-KW-4679 after Oral or Intravenous Administration to Rats.

The absorption, distribution and excretion of 14C-KW-4679 after oral or intravenous administration at a dose of 1 mg/kg were studied in male and female rats. Also the absorption and excretion of 14C-KW-4679 after oral administration at a dose of 25 mg/kg in male rats were studied.1) 14C-KW-4679 was rapidly absorbed and the extent of absorption was estimated to be 91% or higher after oral administration of 1 mg/kg. The drug was presumably absorbed mainly in the region from the duodenum to the jejunum.2) Plasma radioactivity reached Cmax at 0.5 hr after oral administration of 1 mg/kg to fasting male rats and then disappeared biexponentially with terminal half-life of 16.8 hr. By 96 hr after administration, 42.6% and 53.5% of the administered radioactivity were excreted in urine and feces, respectively. In bile, 46.0% of radioactivity was excreted by 72 hr after administration. The excretion of radioactivity in urine, feces and bile almost completed within 24 hr after administration.3) Delayed Tmax and reduced Cmax were observed after oral administration to non-fasting rats compared to fasting rats. There was no significant difference in AUC0-∞. No difference was observed in the excretion of radioactivity in urine and feces, whether animals were fasted or not.4) Larger AUC0-∞ by about 18% was obtained after oral administration to female rats as compared with male rats. A tendency of lower fecal excretion and higher urinary excretion of radioactivity was demonstrated in female rats.5) After intravenous administration of 1 mg/kg to fasting male rats, radioactivity was eliminated from plasma triexponentially with terminal half-life of 34.2 hr. By 96 hr after administration, 51.7% and 43.0%of the administered radioactivity were excreted in urine and feces, respectively.6) Radioactivity was rapidly distributed to almost all tissues after oral administration of 1 mg/kg to fasting male rats. Except digestive organs, higher than in plasma levels of radioactivity were observed in the liver, kidney and urinary bladder. The lowest level of radioactivity was observed in the brain, where the level was about 1/25 of that in plasma, among all the organs examined. Radioactivity in tissues was eliminated almost in parallel with plasma concentration.7) The radioactivity excreted in bile was reabsorbed (8.6%).8) Tmax, dose-normalized Cmax and AUC0-t of plasma radioactivity after oral administration at a dose of 25 mg/kg to fasting male rats was almost equal to that after oral administration at a dose of 1 mg/kg, respectively. Higher urinary excretion of radioactivity after 25 mg/kg dosing than that after 1 mg/kg dosing was observed.

Metabolic Fate of Fluvastatin, an Inhibitor of HMG-CoA Reductase. (2): Transfer to the Fetus and Milk, and Absorption, Distribution and Excretion after Consecutive Oral Administration of (14C)Fluvastatin in Rats.

代謝的に安定なインドール環に[14C]標識したFVを用い，ラットに 1mg/kg で単回経口投与後の胎児および乳汁移行性について検討した．また，[14C]FVを 1mg/kg/day で21日間反復投与した時の血中濃度，分布および排泄について併せて検討を加えた．1．[14C]FVを妊娠12日目および19日目のラットに経口投与後の胎児中の放射能は，投与後6時間で最高値を示し，母獣全血のCm砥のそれぞれ5%および30%を占めたことから，胎児への放射能の移行は妊娠後期に高まる傾向が認められた．2．胎児の各臓器への放射能の分布をみると，主として肝臓および消化管で高く，投与後6時間で最高値を示し，同じ時点の母獣全血とほぼ同等であった．投与後24時間では，消化管内の放射能は母獣全血よりも高値を示し，胎児からの放射能の消失は母獣に比べやや緩慢であった．3．[14C]FVを投与後の妊娠12日目の母獣の臓器・組織内放射能濃度は，非妊娠ラットにおける結果とほぼ同等であった．妊娠19日目のの母獣における放射能の分布は，Cmax 付近で一過性に各臓器・組織内濃度は高まるものの，それ以後の消失および分布パターンは非妊娠および妊娠中期とほぼ同じであった．4．[14C]FVを分娩後14日目の哺育中のラットに経口投与後の乳汁中放射能のほとんどは未変化体であり，投与後8時間で最高値に到達し，血漿の Cmax の約4倍を示したが，血漿とほぼ平行して消失した．5．[14C]FVを 1mg/kg で1日1回，21日間反復経口投与した時の全血中放射能濃度および尿，糞中への排泄率は3～4日目以後ほぼ定常状態に到達した．6．21回投与後の全血の Cmax は初回投与時に比べ1.8倍に増大したものの，tmax，t1/2 および AUC に差は認められなかった．7．定常状態における放射能の各臓器・組織内への分布パターンは初回投与時とほぼ同様であり，特定の組織への残留は認められなかった．8．反復投与後120時間までの尿，糞および呼気中排泄率は，それぞれ総投与量のそれぞれ 2.2%，94.7%，0.1% であり，単回投与時とほぼ同等であった．

260 高吸水性樹脂による放射性同位元素投与患者尿の簡便な採集と測定法

260 高吸水性樹脂による放射性同位元素投与患者尿の簡便な採集と測定法

Studies on the Disposition of Finasteride. (II). Absorption, Distribution, Excretion and Effects on Drug Metabolizing Enzyme System after Repeated Oral Administration to Rats.

The absorption, tissue distribution and excretion of [14C]-finasteride were studied in male rats after repeated oral administration for 22 days at a dose of 5 mg/ kg/day. The effects of finasteride on the drug metabolizing enzyme system in male rats after repeated oral administration for 7 days were also investigated.1. A slight decrease in Tmax and increase in Cmax of the plasma radioactivity were observed after the final administration of [14C]-finasteride, as compared to those after the first administration. Furthermore, t1/2 and AUC values of the last dose were similar to those after the first dose, suggesting that both absorption and excretion rates do not change during the repeated administration.2. No change in the daily excretion of radioactivity in urine and feces was observed during the repeated dosing. Within 96 hr after the last dosing, urinary and fecal excretion of radioactivity were 1.7% and 88.5% of the administered dose, respectively, indicating that the main excretion route is fecal excretion.3. The levels of radioactivity were higher in all tissues at 24 hr after the last dosing than after the first dosing, particularly in fat pad which contained 61 times higher concentration. Although the radioactivity was generally eliminated slower from the tissues after the last dosing than from the plasma, no significant amount of radioactivity was accumulated in the tissues.4. Repeated oral administration of finasteride at doses of 5 and 80 mg/kg/day for 7 days did not have any effect on liver weight, microsomal protein concentration and drug metabolizing enzyme system, except that a moderate and significant increase in aniline p-hydroxylase activity was observed for the high dose group. However, this activity returned to the basal level at 1 week after the last administration.

Metabolic Fate of Fluvastatin, an Inhibitor of HMG-CoA Reductase. (1): Absorption, Distribution and Excretion of (14C)Fluvastatin after Single Administration in Rats.

Fluvastatin (FV) is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Absorption, distribution and excretion of the drug were investigated in rats after single administration of [14C]FV.1. After oral administration of [14C]FV at doses of 0.25, 1, 5, 10 and 20 mg/ kg, the radioactivity in the blood reached the maximum concentration (Cmax) between 1 and 2 hr, and declined with half-lives range of 7 ?? 11 hr. The values of both Cmax and AUC increased in a dose-dependent manner. [14C]FV was absorbed mainly from the intestine, and the extent of absorption was estimated to be 61 ?? 84%.2. Concentration of the unchanged FV in the plasma reached the maximum at 0.5 hr after oral administration of [14C]FV, and decreased with half-life of 3 ?? 4 hr. Bioavailability of the drug was about 46% at 1 mg/kg.3. Distribution of the radioactivity to tissues was rapid and the maximum concentrations were attained within 2 hr after oral administration (1 mg/kg). Majority of the radioactivity was found in the liver and gastro-intestinal contents. At 24 hr, the levels of the radioactivity in the liver and intestinal contents were low, and those in another tissues were negligible.4. Plasma protein binding of [14C]FV was over 97 ?? 99% in rat, dog and human. Binding ratio of [14C]FV to human serum albumin showed to be 94 ?? 97%. After oral administration of [14C]FV to rats, binding ratio of the radioactivity to plasma protein was 97 ?? 99%.5. Excretion of the radioactivity in urine and feces within 144 hr after oral dosing was 4% and 95% of the dose, respectively. In bile duct-cannulated rat, biliary excretion was 83%, and the 58% of the radioactivity excreted into bile was reabsorbed.6. No sex difference was observed in the pharmacokinetic parameters.

Disposition of FK037. (2). Distribution, Metabolism and Excretion of FK037 in Rats after Multiple Intravenous Dosing.

The 14C-labelled compound of FK037 (14C-FK037), a new antibiotics, was intravenously administered in male rats at a dose of 20 mg/kg once a day for 14 days, and its distribution, metabolism and excretion were investigated.1. The radioactivity in the blood collected at 8 hr after 1st, 2nd, 10th and 14th dosing was as follows n.d. (not detected), 0.24, 0.42 and 0.43 μg eq./ml, respectively and attained the steady state after the 10th dosing. The area under the blood concentration-time curves up to infinite (AUC0-∞, 22.6μg eq.·hr/ml) after single intravenous administration was similar to AUC0-24hr after 7th and 14th dosing (19.2 and 24.4μg eq.·hr/ml, respectively).2. Tissue levels of radioactivity in most of tissues at 8 hr after each dosing increased according to the multiple intravenous dosing for 14 days. The radioactivity in the tissues such as kidney, skin, bladder, stomach, lung, brown fat, skeletal muscle, prostate gland and parotid gland at 8 hr after the final dosing was 3.1-5.5 times higher than those at 8 hr after the 1st dosing. The radioactivity in other tissues at 8 hr after the final dosing was 2 times higher than those at 8 hr after the 1st dosing. Tissue concentration of radioactivity at 24 hr after the final dosing was less than 4% of those at 5 min after the final dosing.3. During the multiple intravenous dosing of 14C-FK037, the ratios of unchanged FK037 and metabolites in plasma and urine were not changed. The most of radioactivity in plasma and urine consisted of the unchanged FK037.4. During the multiple intravenous dosing of 14C-FK037, the ratios of urinary and fecal excretion of radioactivity were not changed. The urinary excretion of radioactivity was 94.2 and 94.3% of cumulative doses at 24 and 120 hr after the final dosing, respectively.

Metabolic Studies on CS-670, A New 2-Arylpropionic Acid Nonsteroidal Anti-inflammatory Drug. (1). Absorption, Metabolism and Excretion of 14C-CS-670 in Mice, Rats and Dogs.

14C-CS-670 をラット，マウスおよびイヌに経口投与し吸収，代謝および排泄を検討した．1．マウスに 10mg/kg 経口投与後の血漿中総放射能濃度のTmax は15分，Cmax は 15.8μg/mlで，2時間までのT1/2は 0.41時間であった．血漿中に未変化体は極微量しか存在せず，主代謝物としてcis-OH 体が検出された．2．マウスにおける48時間までの排泄率は尿中に 77.3%，糞中に 14/1% であった．尿中主代謝物は cis-OH 体および trans-OH 体のグルクロソ酸抱合体であった．3．雄性ラットに 2mg/kg 投与後の血液中放射能濃度の Tmax は30分，Cmax は 1.70μg/ml，3時間までの T1/2 は 1.47時間であった．雌性ラットにおけるTmax，Cmax，T1/2 はそれぞれ 30分，3/52μg/ml，2.81時間であった．血漿中に未変化体は非常に少なく，主代謝物として trans-OH 体が検出された．ラット血漿中 trans-OH 体の濃度に，雄性は雌性より低いという性差が認められた．4．雄性ラットでは144時間までの尿中に 72.5%，糞中に 20.7% の放射能が排泄された．雌性ラットでは尿中に 76.7%，糞中に 17.6% が排泄された．尿中主代謝物はジオール体で，雌性(尿中の67.8%)に比べ雄性ラット(尿中の92.8%)で多かった．5．雄性ラットにおける胆汁排泄率は69．5%，再吸収率は 89.5% であった。胆汁中には主に trans-OH 体のグルクロソ酸抱合体として排泄された．6．雄性イヌに 2mg/kg 経口投与後の血漿中 Tmax，Cmax および6時間までのT1/2 はそれぞれ1時間，4.87μg/ml および2.16 時間であった。雌性イヌにおける対応する値は2時間，4.09μg/ml，2.21時間であった．7．雄性イヌでは120時間までの尿中に 57.9%，糞中に 38.9% の放射能が排泄された．雌性イヌでは尿中に 60.6%，糞中に 32.3% が排泄された．尿中主代謝物は雌雄ともにアミノ酸抱合体と推定される極性の強い代謝物で尿中の70-80%を占めていた．8．マウス，ラットおよびイヌにおける CS-670 の代謝には顕著な種差が観察された．すなわち，いずれの動物でも CS-670 の二重結合が速やかに還元されたのち，ケトン基が還元されラットおよびイヌでは trans-0H 体が，マウスでは cis-OH 体が主に生成するが，それらモノオール体をラットはジオール体として，マウスはグルクロン酸抱合体として，またイヌはアミノ酸抱合体と推定される代謝物として尿中に排泄した．さらに，ラットではジオール体の生成に雌性に比べ雄性で多いという性差が認められた．

Identification of urinary metabolites of ecabapide in rat.

1. 14C-Ecabapide, 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]amino-N- methyl[14C]benzamide, was dosed orally to rat (100 mg/kg). Within 48h after dosing, 36.7 +/- 5.4 and 55.7 +/- 11.8% of the administered radioactivity was recovered from urine and faeces respectively. 2. The unchanged drug was the major compound excreted in the urine and accounted for 37% of the urinary radioactivity. Seven urinary metabolites were purified by preparative hplc and their structures were elucidated by mass and 1H-nmr spectrometry. 3. The major metabolic pathway of ecabapide was found to be the formation of 3-amino-N-methylbenzamide produced by N-dealkylation of the secondary amine at the 3-position of the benzamide moiety followed by acetylation. 4. Further metabolic pathways of the N-methylbenzamide moiety were N-demethylation via the carbinolamine derivatives, and/or aromatic hydroxylation followed by glucuronidation.

Enantioselective metabolism and pharmacokinetics of Casodex in the male rat.

1. Casodex, a non-steroidal antiandrogen, is a racemic mixture of R-Casodex, the pharmacologically active (-)-enantiomer, and S-Casodex, the inactive (+)-enantiomer. Single oral doses of pseudo-racemic 14C-Casodex (10 mg/kg), prepared from mixtures of either 14C-labelled R-Casodex and unlabelled S-Casodex, or 14C-S-Casodex and unlabelled R-Casodex, were administered to the intact and bile duct-cannulated male rat. 2. Neither enantiomer underwent stereochemical inversion, but the pharmacokinetics of Casodex showed marked enantioselectivity. 3. After dosing R-labelled Casodex, plasma concentrations of R-Casodex increased slowly to reach a peak of 3.50 +/- 0.05 micrograms/ml (mean +/- SEM) at 12 h and, thereafter, declined monoexponentially with an elimination half-life of 24 h. Plasma concentrations of S-Casodex rose rapidly to reach a much lower peak of 0.97 +/- 0.06 microgram/ml at 3 h and, thereafter, declined rapidly, although there were insufficient data to determine the half-life. R-Casodex had a much higher AUC0-24 (66 micrograms.h/ml) than S-Casodex (12 micrograms.h/ml). Plasma drug concentrations measured using an achiral assay were in very good agreement with the sum of the enantiomer concentrations throughout the profile. R-Casodex comprised 94% of the total plasma radioactivity at 12 h, decreasing to 75% at 120 h. 4. Plasma concentration data generated after administration of S-Casodex were similar to those observed after dosing R-labelled Casodex. S-Casodex comprised about 74% of the total plasma radioactivity at 6 h and only 41% at 24 h. 5. The urine of intact animals contained 36 +/- 2 and 48 +/- 3% of the dose respectively up to 48 and 120 h after dosing with R-labelled Casodex, and 33 +/- 4 and 34 +/- 4% respectively after dosing with S-labelled Casodex. The urine and bile of the cannulated rat contained 43 +/- 2 and 21 +/- 2% of the dose respectively up to 48 h after dosing with R-labelled Casodex and 37 (n = 2) and 50% respectively after dosing with S-labelled Casodex. 6. After dosing with R- or S-labelled Casodex, the urinary radioactivity consisted of the carboxylic acid metabolite formed by hydrolytic cleavage at the amide, whereas biliary radioactivity consisted of hydroxy-Casodex and Casodex, mainly conjugated with glucuronic acid. The clearance of R-Casodex by each of these pathways of metabolism was less than that of S-Casodex, with direct glucuronidation and hydroxylation showing greater enantioselectivity than hydrolysis.

Disposition and metabolism of radiolabelled pentachloroanisole in rats and rabbits

Male Sprague-Dawley rats and New Zealand White rabbits were administered 14C-labelled pentachloroanisole (PCA) in corn oil by gavage as single doses of 25 mg/kg and were then placed in individual metabolism cages for as long as 4 days. Peak blood level of radioactivity occurred 6 hr after administration of the dose to rats and between 3 and 4 hr in rabbits; the blood elimination half-life ranged from 8 to 15 hr in rats and averaged 6 hr in rabbits. Rats excreted an average of 54.2% of the administered radiolabel in the urine and 32.4% in the faeces during the 96 hr following the dose; rabbits excreted an average of 84.2 and 13.1% of the radiolabel in the urine and faeces, respectively, during this time. Examination of the metabolites in the rat showed that 60% of the urinary radioactivity was attributable to tetrachlorohydroquinone (TCH). 3% to free pentachlorophenol (PCP) and 29% to conjugated PCP; faecal metabolites were PCP (85.7%), TCH (4.3%) and polar metabolite(s) (10%). In the rabbit, 58% of the urinary radioactivity was attributable to TCH. 8% to free PCP and 34% to conjugated PCP. Faecal metabolites consisted of PCP and conjugated material.