Distribution and excretion of N-Ile1 Thr2-63-desulfatohirudin in rats
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Objective To investigate distribution and excretion of N-Ile1Thr2-63-desulfatohirudin(rH)a recombinant hirudin newly developed in China,in rats for its development as a novel anticoagulant agent.Methods ELISA was used to determine the rH concentration in related tissues and body fluids.Tissues were collected at 15,60 and 180min respectively,after iv administration of rH 1.0 mg·kg-1 to 3 groups of 5 rats,and homogenized.Urine,bile and feces were collected at pre-selected intervals of time after iv dosing 1.0 mg·kg-1 to 3 groups of 5 rats and assayed.Results rH following iv dosing was distributed rapidly,the rH levels in all tissues being found to be the highest at 15 min post-injection,afterwards gradually reduced.The highest concentration of rH was found in blood,the next in lung and heart,the lowest in brain.With 15 min post dose as an example,the rH contents in tissues were ranked in order of plasmalungheart adiposeskeletal muscleskidneyliverspleenbrain.The 12 h-cumulative excretion amount of rH in urine and feces accounted for 0.03%and 0.001% of administered dose,respectively;the 6 h-cumulative excretion amount in bile was 0.02%of the dose.Conclusions The rH is distributed mainly in blood circulation system with very low content in other tissues.The drug is excreted from urine,feces and bile of rats in extremely minute amount(only 0.051% dose),suggesting that rH undergoes extensive metabolic elimination in rat body.Cite
9-Amino-8-fluoro-1, 2, 3, 4-tetrahydro-2, 4-methanoacridine citrate (SM-10888) was given to rats orally or intravenously, and its absorption, distribution and excretion were investigated. 1. After a single oral administration of 14C-SM-10888 (5mg/kg), the serum 14C level reached a maximum at 30min (1.09μg eq./g), with an AUC value corresponding to about 90% of that observed after intravenous administration, clearly revealing rapid and efficient absorption from the gastrointestinal tract. Under fasted conditions, Cmax was 2-fold higher than that of non-fasted animals, without significant change in AUC, suggesting that diet causes delayed absorption. Both Cmax and AUC increased as the dose was raised from 1 to 20mg/kg. Repeated dosing (5mg/kg/day for 14 days) exerted little effect on serum 14C levels. 2. After a single oral administration of 14C-SM-10888 (5mg/kg), the radioactivity was distributed throughout the body, with relatively higher activities being observed in the digestive tract, the liver and the salivary gland. Radioactivity in each tissue had drastically decreased by 24hr post administration. 3. After a single oral administration of 14C-SM-10888 (5mg/kg), cumulative excretion into the urine and feces after 168hr was 52.2% and 44.2%, respectively. When administered to bile-duct cannulated rats, cumulative excretion after 72hr into the bile and urine was 65.1% and 29.1%, respectively, providing further support for a high absorption rate. Repeated dosing had little effect on the patterns of excretion into the urine and feces.
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雄性ラットに14C-ミルリノンを5mg/kg単回および反復静脈内投与したときの血漿中濃度，分布および排泄について検討した． 1．14C-ミルリノンをラットに単回静脈内投与したときの血漿中放射能濃度は2相性で低下し，最終消失相のt1/2は3.5hrであった．AUC0-∞，VdssおよびCLtotalはそれぞれ7.19μg equiv. ofmilrinone·hr/ml，873ml/kgおよび11.6ml/min/kgであった．血漿中の未変化体濃度は放射能濃度とほぼ同様の値で推移し，t1/2，AUC0-∞，VdssおよびCLtotalはそれぞれ3.2hr，7.35μg·hr/ml，727ml/kgおよび11.3ml/min/kgであった． 2．14C-ミルリノンを単回静脈内投与したときの放射能は各組織へ速やかに分布し，投与後15分に最高濃度を示した．投与後15分の組織内濃度は腎において血漿より約4倍高い値を示したが，他の組織ではいずれも血漿と同程度かそれ以下であった．その後，放射能は皮膚を除く各組織から速やかに消失した．14C-ミルリノンを7日間連続静脈内投与したときにはいずれの組織においても放射能の蓄積性は認められなかったが，皮膚からの消失が比較的遅かった．投与後24時間の全身オートラジオグラムにおいて放射能は被毛で認められたが，皮膚では検出されなかった．被毛では投与後72時間にも弱い放射能が検出された． 3．14C-ミルリノンを単回静脈内投与後168時間までの放射能の尿および糞中排泄率はそれぞれ79.2%および21.9%であり，投与量の101.1%が回収された．14C-ミルリノンを7日間連続静脈内投与したとき，放射能の尿および糞中への累積排泄率はそれぞれ74.9%および21.4%と単回投与時と同様であった．胆管カニューレを施したラットに14C-ミルリノンを単回静脈内投与後48時間までの尿，糞および胆汁中へ放射能がそれぞれ65.1%，10.4%および18.9%排泄され，本薬の主排泄経路は腎排泄であることが示された．
Milrinone
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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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Gallanilide 20 mg/kg iv in rats showed its distributing levels as follows: high in lung and kidney; spleen, gastrointestinal tract, liver, heart, testis and blood the next; brain the least. It folloxved a pattern or two-compartment model in rat. After 20 mg/kg im over a 24-h period, 2.4% of the dose was found in the urine. 0.08% in the feces, and 0.15% in bile excretion 5 h after iv 20 mg/kg. The ig (introgastric) and ir (rectal) absolute bioavailability of gallanilide was 19 and 28% respectively, while the relative bioavailability was 67% (p<0.05).
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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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The absorption, distribution, metabolism and excretion of radioactivity were investigated after a single oral administration of 14C-felodioine 1 mg/kg to does of both sexes. 1. Radioactivity concentration in the plasma of male dogs reached a Cmax of 2, 228ng eq./ml at 2hr and then declined with half-lives of 4.8hr up to 8hr, 16hr from 12hr to 48hr and 123hr from 72hr to 168hr after administration. Radioactivity concentrations in the blood were 51 ?? 62% of those in the plasma. The AUC0-∞ was 41.3μg•eq. hr•ml-1. Profiles of radioactivity concentrations in the blood and plasma of female dogs were similar to those in male dogs. 2. In male dogs, 54.9 and 41.4% of the dose was excreted in the urine and feces within 168hr, respectively. In female dogs, 55.8 and 38.9% of the dose was excreted in the urine and feces within 168hr, respectively. The excretion of radioactivity was not sex dependent. 3. In the plasma, the parent compound was a minor substance and M-III and M-IV were mainly found. In the urine, M-III, M-IV and M-V were the major metabolites, while in the feces, M-III, M-IV, M-VI (lactone) and M-VII (lactone) were mainly found. Hardly any sex difference was present in the relative amounts of metabolites in the plasma, urine and feces. The major metabolites UM1 and UM2 found in the plasma of rats were not present in the plasma of dogs.
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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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[14C] Bermoprofenを主として3mg/kgの用量で，単回経口または静脈内投与後のラットにおける体内動態を検討した． Bermoprofenは主に小腸全域で吸収されることが示唆された．経口投与後と静脈内投与後との尿中排泄率の比較により，経口吸収率はほぼ100%と推定された．全血中放射活性濃度は経口投与後30分で約2.0μg eq./mlと最大に達し，以後半減期2.6時間で消失した． 大部分の組織中放射活性濃度は経口投与後1時間で最大となった．放射活性の移行が最も高かった組織は腎臓で血漿中濃度の約2.8倍，次いで肝臓(0.69倍)であり，そのほかの組織中濃度は血漿中濃度の1/3以下であった．中枢神経系への移行は極めて低かった．胎仔，乳汁中放射活性濃度は母体血漿中濃度の0.07，0.18倍と低かった．血清蛋白結合率は99.6%であった． 経口あるいは静脈内投与後，尿中に約70%，糞中に約30%の放射活性が排泄された．胆汁中へは約46%が排泄され，このうち約46%が再吸収されると考えられる． Bermoprofenはメチル基の酸化，カルボニル基の還元，プロピオン酸基の抱合により代謝されるが，ラットにおいてはメチル基の酸化が主代謝経路であった．
Disposition
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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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雄ラットに14C標識フマル酸セモチアジル(SD-3211)を経口あるいは静脈内に単回投与した場合の吸収，分布，代謝および排泄について検討した．1．経口投与後の血漿中の放射能は，投与後1時間にCmaxO.26μg/mlを示した後，半減期6.4時間で消失した．また，血漿中未変化体も同様に，投与後1時間にCmax0.13μg/mlとなった後，半減期3.5時間で消失した．2．経口投与後ほとんどの組織において，放射能濃度は2～6時間で最高濃度に達した．その中でも肝臓，肺，腎臓およびハーダー腺が比較的高濃度であった。投与後96時間では，すべての組織において，その最高値に比べ非常に低濃度となった．3．経口投与後96時間までに，糞中へ93.8%，尿中へ1.2%が排泄された．また，静脈内投与では，投与後96時間までに，糞中へ93.0%，尿中へ5.6%が排泄された．4．経口投与後48時間までに，胆汁中へ87.3%が排泄された．同様に，静脈内投与では，投与後48時間までに胆汁中へ88.6%が排泄された．5．血漿，肺および腎臓では，投与後6時間まででは，未変化体が組織中放射能の37～58%を占めた．しかし，肝臓では未変化体の存在率は低かった．胆汁，糞および尿中では未変化体はほとんど検出されなかった．
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