Tissue Distribution and Excretion of Radioactivity in Mice After Intragastric Administration of ~3H-β,β-dimethylacrylshikonin
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Tissue distribution and excretion of radioactivity in mice after intragastric admin- istration of ~3H-β,β-dimethylacrylshikonin were investigated.Tissues and feces were com- busted by sample Oxidizer,the subsequent radioactivity measurements were carried out af- ter addition of scintillator to the combusted samples and urine.The results showed that the radioactivity in gastrointestinal system was higher than that in the liver,lung,kidney and heart,while that in skeletal muscle,spinal cord,brain was lower.After single intragastric administration(chemical dose 84.0 mg/kg,radioactive dose 22.3 MBq/kg)ofβ,β-dimethy- lacrylshikonin to mice,the cumulative radioactivity excretion rate of urine and feces were (8.43±0.26)% and(72.87±9.92)% respectively within 336 h ,the total excretion rate was(81.30±9.79)%.The samples of plasma,feces and urine were also analyzed by HPLC.The rsult is that parent drug mainly existed in feces,not in plasma or urine.This study showed that ~3 H-β,β-dimethylacrylshikonin was distributed widely in mice,and excre- ted mostly through fecal route and secondarily via urine.Cite
In 10 patients, 5 having received 3H-cymarol i.v., 5 orally, the radioactivity in plasma, urine and in the feces of some patients also was determined. After oral administration the plasma levels rose rapidly reaching maximum levels 1--2 h after administration. After i.v. injection about 30% of the given radioactivity were excreted in the urine. The remaining radioactivity was found in the feces suggesting a high biliary excretion. Only 10% of the radioactivity excreted in the first 24 h were chloroform-extractable. The radioactivity found in the urine after oral administration of the drug amounted to 17.6%. Between 51.1 and 58.5% of the drug were bound to serum proteins.
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To study the tissue distribution and excretion of bromotetrandrine (W198) in rats.The concentrations of W198 in biological samples were determined by an HPLC method with UV detection.After a single i.v. dose of 20 mg x kg(-1) W198 in rats, the parent drug concentrations in tissues were higher than those in blood at the same time. Parent drug was mainly distributed in lung, kidney, heart and liver, the peak levels were attained at 0.25 h and decreasing at 2 h after dosing in most tissues. After a single iv dose of 20 mg x kg(-1) W198 in rats, the excretion of the parent drug in urine, feces and bile amounted to 0. 150%, 2.1% and 0.063% of the dose, respectively.W198 was mostly distributed in lung. The parent drug excretion was less than 3% via urine, feces and bile.
Tissue distribution
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14C-ONO-5046·Naをラットに単回静脈内投与後の血漿中濃度-時間推移，分布および排泄について検討した． 1．雄性ラットに14C-ONO-5046·Naを静脈内急速投与(0.1から100mg/kg)すると，消失相における半減期は163.61から192.72分であった．1mg/kgまではAUC0-∞は用量に比例して増加した．0.1から100mg/kgまでの投与量では雌雄間の動態パラメータに大きな差はなかった． 2．雄性ラットに14C-ONO-5046·Naを0.1，1および10mg/kg/hrの速度で3時間静脈内持続投与した時，血漿中放射能はおよそ1.5時間で定常状態に達していた．また，定常状態の血漿中放射能濃度およびAUC0-∞は用量に依存して増加しており，消失半減期は232.29から631.63分であった． 3．雌雄ラットに1mg/kgの用量で静脈内急速投与後30分において放射能は全身に分布し，腎臓，小腸および小腸内容物に高濃度の放射能が認められた．投与後24時間では放射能はほとんどの組織で定量限界となり，残留性を示す臓器は認められなかった． 4．雄性ラットに14C-ONO-5046·Naを1mg/kgの用量で静脈内急速投与した後，24時間の糞および尿中排泄率はそれぞれ24.0および73.1%であった．投与後72時間までに尿と糞に排泄された総放射能は投与量の99.4%であった．一方，雌性ラットでは投与後24時間で糞および尿に排泄された割合はそれぞれ8.2および91.9%と雌雄差が認められた． 5．雌雄ラットに14C-ONO-5046·Naを1mg/kgの用量で静脈内急速投与した時，2時間までの胆汁排泄率はそれぞれ33.0および14.0%であり雌雄差が認められた．また，投与後48時間までの累積排泄率はそれぞれ35.9および15.4%であった．胆汁中の放射能のほとんどが投与後2時間までに排泄された． 6．14C-ONO-5046·Naを1mg/kgの用量で静脈内急速投与し排泄された胆汁を受容ラットの十二指腸内へ注入し，胆汁および尿へ回収された放射能から求めた再吸収率は雄および雌性ラットでそれぞれ38.9および42.5%であった．
Neutrophil elastase
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[14C]TZU10mg/kg をラットに静脈内投与し，生体内分布，尿，糞および胆汁中排泄，さらに血中推移について総放射能および主代謝物の両面から詳細に検討し，以下の結論を得た．1．主代謝物であるM-1，M-2およびM-3の定量に LC/MS-SIM を用いることにより，従来の GC/MS 等による測定に比べ，3化合物の定量を精度よく短時間に，かつ同時に行うことが可能となった．2．血液中総放射能および血漿中M-1濃度はいずれも2相性に減少し，α相のT1/2はそれぞれ 0.38，0.17時間，β相で3.82，0.77時間であった．血漿中M-2およびM-3濃度の T1/2 はそれぞれ 1.36，0.91時間であった．3．[14C]TZUの体内分布では，肝臓，腎臓のような代謝および排泄組織，胃および小腸のような作用組織，あるいは耳下腺，顎下腺などの分泌組織において総放射能が高いが，ほとんどの組織においてその消失は速やかであり，72時間後までに投与量の 0.1%以下あるいは検出限界以下となった．4．主要組織の radio-HPLC 分析パターンより，投与15分後では，肝臓を除く4種の組織(脳，胃，小腸および腎臓)で，放射能がM-1，M-3，M-2画分の順で高く，それらの合計は総放射能の大半を占めていた．よってこれら3種が TZU の主代謝物であり，時間の経過に伴い酸化的代謝あるいは抱合を受けて極性の高い画分へ移行することが判明した．5．主要7組織について，ラット尿中における3種の主代謝物(M-1，M-2およびM-3)濃度を LC/MS-SIM により定量した結果，3代謝物ともに，精巣を除くすべての組織で T1/2 が 3.4時間以下と速やかな消失を示した．6．精巣での総放射能の T1/2 は 10.5時間と比較的長く，これはM-2およびM-3に基づくものと判明した．7．TZU の薬効の標的組織である胃および小腸では，薬理活性を有する代謝物であるM-1が最も高濃度であり，すぐれた H2拮抗薬としての特徴が認められた．8．肝臓においてはM-3の濃度が非常に高いことから，酸化的脱アルキル化でフェノール体(M-3)が，主として肝臓で生成することが確認された．9．投与48時間後までに投与した放射能の約87%が尿中に，約8%が糞中にそれぞれ排泄された．尿中の主代謝物はM-3であり，その約半分は抱合体であった．糞中ではこれら3代謝物の排泄比率は投与量の 0.3% とほぼ同等であった．10．胆痩ラットでは投与後48時間までに投与した放射能の 20% が胆汁に排泄された．M-1，M-2画分の放射能はいずれも投与量の0．3%であるのに対し，M-3画分は約8%と最も高く，そのほとんどが抱合体であった．
Hydrochloride
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ラットに14C-YM060を1mg/kg静脈内投与した時の血中濃度，分布および排泄について検討した． 1)全血中放射能濃度は2相性で低下し，消失相の半減期(t1/2)は78.0分であった．血漿中放射能濃度は投与後5～15分までほぼ同程度の濃度で推移し，その後79.8分の半減期で低下した．血漿中未変化体濃度は2相性で低下し，t1/2は36.6分であった．全血中放射能，血漿中放射能および血漿中未変化体のAUC0-∞はそれぞれ398.7，412.6ng equiv. ·h/mlおよび123.6ng·h/mlであった． 2)放射能は速やかに全身に分布し，組織内濃度は大部分の組織で投与後5分に最高値を示した．放射能濃度は腎臓が最も高く，次いで肺，肝臓，副腎，膵臓，脳下垂体，顎下腺，胃，小腸の順であり，脳が最も低かった．放射能は組織から速やかに消失し，ほとんどの組織において投与後24時間の濃度は最高値の1.2%以下であった． 3)投与後72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29.7%および70.9%であり，投与した放射能は完全に体外に排泄された．胆管カニューレを施したラットにおいて投与後72時間までの胆汁および尿中放射能排泄率は，投与量のそれぞれ67.2%および31.1%であった．胆汁中に排泄された放射能のうち33.5%が再吸収された．
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After oral administration of [4-(3)H]EGCg to rats, the radioactivity in blood, major tissues, urine, and feces was measured over time. The radioactivity in blood and most tissues remained low for 4 h postdose, began to increase after 8 h, peaked at 24 h, and then decreased. Major urinary excretion of radioactivity occurred in the 8-24 h period, and the cumulative radioactivity excreted by 72 h was 32.1% of the dose. The radioactivity in the feces was 35.2% of the dose within 72 h postdose. In the case of rats pretreated with antibiotics (antibiotic-pretreated rats), the radioactivity levels of the blood and urine were definitely lower than those in rats not pretreated with antibiotics (normal rats). The radioactivity recovered in the antibiotic-pretreated rat urine was estimated to be only (1)/(100) of that in the normal rat urine. These results clearly demonstrated that the radioactivity detected in the blood and urine of normal rats mostly originated from degradation products of EGCg produced by intestinal bacteria. Furthermore, a main metabolite in the normal rats was purified and identified as 5-(5'-hydroxyphenyl)-gamma-valerolactone 3'-O-beta-glucuronide (M-2). In feces of the normal rats, EGC (40.8% of the fecal radioactivity) and 5-(3',5'-dihydroxyphenyl)-gamma-valerolactone (M-1, 16.8%) were detected. These results suggested that M-1 was absorbed in the body after degradation of EGCg by intestinal bacteria, yielding M-1 with EGC as an intermediate. Furthermore, M-2 was thought to be formed from M-1 in the intestinal mucosa and/or liver, then to enter the systemic circulation, and finally to be excreted in the urine. Taking into account all of the above findings, a possible metabolic route of EGCg orally administered to rats is proposed.
Glucuronide
Intestinal bacteria
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The absorption, distribution, metabolism and excretion of 14C-KT1-32 were studied after a single oral and intravenous administrations in the doses of 4-100mg/kg to male and female rats, and male mice.1. The radioactivity in plasma reached a maximum concentration at 4.5hr (48μg equivalent KT1-32/ml) after oral administration of 14C-KT1-32 to male rats in a dose of 20mg/kg and then declined with half-life of 3.9hr.2. The levels of radioactivity in plasma reached a maximum concentration at 3.3hr after oral administration of 14C-KT1-32 to female rats in a dose of 20mg/kg and then declined with half-life of 3.7hr.3. The excretion of radioactivity amounted to 57% of the dose in urine and 43% of the dose in feces within 96hr after oral administration to male rats in a dose of 20mg/kg, while after intravenous administration to male rats, the excretion of radioactivity were found to be 81% and 17% of the dose in urine and feces, respectively.4. The biliary excretion within 48hr after oral administration of 20mg/kg corresponded to 7.7% of the administered dose to male rats, while the excretion of the radioactivity reabsorbed, amounted to 5.3% of the dose in the bile within 48hr after intraduodenal injection.5. After 20mg/kg oral administration, the female rats excreted during 96hr 73% and 28% of the dose in urine and feces, respectively.6. The radioactivities in the tissues, except the gastro -intestinal tract and fat, reached the maximum concentration at 3hr after oral administration of 20mg/kg to male rats and relatively high radioactivities were found in the blood, liver, kidney and lung. The radioactivities in all tissues were decreased to less than 17% of the highest concentration at 72hr after oral administration.7. In female rats, after oral administration of a dose of 20mg/kg, the concentrations in the tissues were lower than that in male rats.8. After oral administratrion of a dose of 20mg/kg, Ml, M2, M4 metabolites and the intact drug were the major components and M-3, M-5 and M-6 were also detected, however as the minor compounds, in the 0-24hr urine collected from male rats.9. The M1, M2 metabolites and intact drug were also found in the 0-24hr fractions of bile in male rats.
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The tissue distribution and excretion of 2,4-[14C]toluenediamine was studied in male mice given a single ip dose (1 microCi, 0.667 mg/kg). By 24 h 52% of the administered radioactivity had been excreted in the urine and 22% in the feces. The organs with the highest concentrations of radioactivity were the liver and kidneys. High concentrations of radioactivity were also observed in the gastrointestinal tract. Elimination of radioactivity from the liver, kidneys, and blood was biphasic, with half-lives of 11.7, 9.1, and 12.6 h, respectively, for the slow phases. The dominant route of excretion was via the kidneys; during the first hour after dosing, nearly 50% of the administered radioactivity was recovered in the urine. However, only an additional 2-4% of the dose appeared in the urine during the remaining 23 h of the experiment. By 24 h, only 1.25% of the administered radioactivity has been trapped from the air expired by the animals.
Tissue distribution
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[3H]Kakuol given intragastrically was rapidly absorbed from gut of mice and rats. It was rapidly taken up by various organs,and has a strong affinity for tissues. The highest radioactivity was found in liver(12.1 time as much as in plasma), followed by heart, spleen, pancreas, kidney, lung and brain. The radioactivity in organs disappeared slowly. In 21 d, cumulative excretion of radioactivity was 92.8% of the total dose in urine and 1.2% in feces. The results measured by TLC autoradiography and liquid scintillation counting in urine indicated that[3H] kakuol was excreted mainly in urine in unchanged form. The rate of binding with plasma protein was 39%. After iv in mice, the decline of radioactivity in the plasma showed a biphasic curve. Pharmacokinetic parameters:t(1/2 alpha)=0.21 h, t(1/2 beta)=40 h, Vc=2.3 L/kg, Vd=26.5 L/kg.
Liquid Scintillation Counting
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The absorption, distribution, excretion and metabolism of 14C labelled 2-chlorophenyl-1-phenyl-3-(2 methyl-piperidino) propyl ether methyl iodide (14C-R97) were studied by means of direct measurement of radioactivity and autoradiographic technique in rats. 1) With intravenous administration, radioactivity was found in all the tissues and organs immediately after dosing, with particularly high levels in the liver, kidney, heart and lung. Five minutes after administration, the level of radioactivity in blood decreased to about 6% of the initial level, indicating the rapid absorption of radioactive material by other tissues and organs. Radioactivity was not detected in the brain and eye. Thirty minutes after administration, the concentration of radioactivity in the gastrointestinal contents was very high and a certain amount of radioactivity uptake was noted both in gastric and intestinal mucosa. Approximately 12% and 40% of radioactivity administered was excreted in the urine and feces respectively during the first 24 hours, however, the excretion of radioactivity by expiration was not determined. 2) With oral administration, radioactivity was restricted to the gastrointestinal tract. Activities in other tissues and organs were not detectable. Approximately 94% of the radioactivity administered was recovered in feces during the first 24 hours. 3) Radioactivity was not observed in either the foetus or placenta after both intravenous and oral administrations. 4) The results from autoradiographic study were in good accord with those described above.
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