薬物動態
Print ISSN : 0916-1139
12 巻, 1 号
選択された号の論文の8件中1~8を表示しています
  • Ken-ichi SHINODA, Hitoshi SATO, Isao ADACHI, Isamu HORIKOSHI
    1997 年 12 巻 1 号 p. 1-4
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    We have recently reported that cepharanthine (CEP) incorporated in liposomes increased IgM antibody production to a greater extent than CEP solution [Shinoda, et al.; Drug Delivery System, 10: 43-48 (1995)]. In order to provide some insights into the relationship between the immuno-modulating activity of liposomal CEP and its biodistribution, this study examined the disposition of liposomal CEP after intraperitoneal (i.p.) administration to mice in comparison with CEP solution. The liposomes were composed of egg phosphatidylcholine and cholesterol in a molar ratio of 7 : 2. Multilamellar liposomes (MLV) were prepared by vortexing dried lipid films, and small unilamellar liposomes (SUV) by ultrasonication of MLV. CEP-containing liposomes and CEP solution (as a control) were injected intraperitoneally to mice. The half-life and mean residence time of CEP were longer after administration of liposomal CEP compared with CEP solution. After CEP injection in liposomes or solution, the mean transit time of CEP in the spleen was higher than those in the liver and lung. However, the liposomes containing CEP reduced the tissue distribution of CEP into the liver, lung, and spleen, compared with CEP solution. In conclusion, it was suggested that immuno-modulating action of CEP may not be directly related to the in vivo disposition of CEP.
  • 恒川 健, 今若 治夫, 藤本 博昭, 石堂 雅恒, 柴川 公雄, 平工 誠治
    1997 年 12 巻 1 号 p. 5-21
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    ONO-1101をラットに単回静脈内急速投与あるいは静脈内定速注入時の血中動態,分布,排泄について検討した.
    1.雌雄ラットに14C-ONO-1101を0.3,1,3,10mg/kgの用量で静脈内急速投与した時の,血漿中総放射能濃度推移から求めた無限大までのAUCは用量に応じた増加が認められ線形性が確認された.消失相の半減期は27~33分であり,雌雄差は認められなかった.
    2.14C-ONO-1101を1mg/kgの用量で静脈内急速投与したときの組織中放射能は,投与初期(5,15分)で腎臓,肝臓,肺,気管で高濃度であり,皮膚,各組織・臓器採取後の死骸において分布量が多かったが,経時的に減少し投与後24時間では検出限界以下あるいはきわめてわずかな放射能濃度となった.中枢,胎児への移行はほとんど認められなかった.
    3.乳汁への放射能の移行は投与後1時間で最高濃度(278.8ng eq/ml)に達し,投与後24時間には放射能濃度は2.4ng eq/mlであった.
    4.静脈内急速投与された14C-ONO-1101の投与72時間までの尿中排泄率はそれぞれ雄85.6%,雌84.2%であった.また,投与72時間までの糞中への排泄率は雄9.9%,雌12.0%であった.
    5.14C-ONO-1101を1mg/kgの用量で静脈内急速投与後の胆汁排泄率は24時間までに雄6.1%,雌9.5%が排泄され雌雄差が認められた.
  • 恒川 健, 今若 治夫, 夏井 潔, 藤本 博昭, 石堂 雅恒, 柴川 公雄, 平工 誠治
    1997 年 12 巻 1 号 p. 22-30
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    ONO-1101を反復静脈内投与時の血中動態,分布,糞尿排泄および肝薬物代謝酵素に対する影響について検討した.
    1.雌雄ラットに14C-ONO-1101を1mg/kgの用量で1日1回7日間反復投与した時,各回投与後24時間の血漿中放射能濃度は検出限界以下,あるいは検出限界付近のきわめて低い濃度であり,最終回投与後の血漿中濃度推移は雌雄ラットとも単回投与時とほぼ同じであった.
    2.雄性ラットに14C-ONO-1101を1mg/kgの用量で1日1回7日間反復投与した時の最終回投与後の各組織中放射能濃度は,投与初期(5,15分)には腎臓,肝臓,肺,気管において高濃度であり,皮膚,各組織・臓器採取後の死骸に分布量が多かったが,それ以降は経時的に減少した.代謝,排泄臓器である肝臓,腎臓では単回投与時と比べてわずかに高い値を示したが,特定の組織・臓器への放射能の残留は認められなかった.
    3.雌雄ラットにONO-1101を1mg/kgの用量で1日1回7日間反復投与後の尿および糞中への累積排泄率は4日目以降からほぼ一定の値となり,最終回投与後96時間まででそれぞれ雄性で89.7,14.9%,雌性で86.5,17,0%であった.
    4.雄性ラットにONO-1101を1,10,50mg/kgの用量で1日1回7日間反復投与した時の肝薬物代謝酵素に対する影響は認められなかった.
  • 恒川 健, 今若 治夫, 山本 勝彦, 柴川 公雄, 平工 誠治
    1997 年 12 巻 1 号 p. 31-41
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    ONO-1101をラットおよびイヌに静脈内投与した時の代謝について検討した.また,ONO-1101のin vitro代謝速度における種差,ONO-1101のヒト血漿中の水解代謝に対するエステル基を有する薬剤による影響および蛋白結合についても検討した.
    1.ラットに静脈内投与後5分の血液中放射能は81.8%がONO-1101のエステル結合が水解されたM-1として存在し,未変化体は2.1%であった.静脈内投与後の尿中および胆汁中の主代謝物もM-1であり,未変化体は7.0%以下であった.
    2.イヌに静脈内投与後5分の血漿中には未変化体およびM-1がそれぞれ1.87μg/mlおよび1.35μg/ml存在した.投与後30分には未変化体,M-1以外にM-1のβ酸化体であるM-2が認められた.M-1,M-2および未変化体は,静脈内投与後24時間までの尿中にそれぞれ投与量の38.1%,40.5%および2.7%が排泄された.胆汁中には投与後8時間までにM-1および未変化体がそれぞれ投与量の0.10%および2.83%排泄された.
    3.ラット,イヌおよびヒト血漿におけるONO-1101の水解活性はラット,ヒト,イヌの順に強く,ONO-1101の水解代謝に関与するヒトの血漿のエステラーゼはpseudocholinesterase,ラットの血漿,肝臓およびイヌの肝臓のエステラーゼはcarboxylesteraseと考えられた.
    4.アセチルコリン,エナラプリルはヒト血漿中でのONO-1101の水解代謝に対して影響を与えなかったが,pseudocholinesteraseにより水解代謝されるプロカイン,サクシニルコリンはONO-1101の水解代謝を競合的に阻害した.
    5.ONO-1101の血清蛋白結合率は0.1μg/mlの濃度においてラット,イヌおよびヒトでそれぞれ2.8,21.3,1.6%であった.
  • 恒川 健, 阪口 喜美子, 夏井 潔, 中尾 康弘, 柴川 公雄, 平工 誠治
    1997 年 12 巻 1 号 p. 42-47
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    ONO-1101 ((−)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbonylamino)ethylamino]propoxy]phenylpropionate monohydrochloride)をイヌに静脈内急速投与後の血中動態および静脈内定速注入後の血中動態を検討し,さらに麻酔の影響について検討した.
    1.ONO-1101を0.3および3.Omg/kgの用量で静脈内投与した時,血漿中の未変化体はいずれの投与量においても速やかに消失し,AUC0-∞は用量に応じた増加が認められた.代謝物としてM-1,M-2が認められ,これらの消失は緩慢であった.
    2.麻酔下に静脈内定速注入した時,薬物動態パラメータには有意差は認められなかったが,麻酔下では無麻酔下に比べ未変化体の血漿中濃度は高く推移した.
  • Yoshihisa SANO, Kyoichi TADANO, Kazuhiro KANEKO, Kiyomi KIKUCHI, Terua ...
    1997 年 12 巻 1 号 p. 48-57
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    [14C]menaquinone-4, a therapeutic agent for osteoporosis, was administered orally to male dogs at a dose of 4 mg/kg, and the absorption, distribution, metabolism and excretion were investigated.
    1. The plasma concentration of radioactivity reached the maximum level (Cmax) of 4540.4 ng eq./ml at 1 to 2 hours after administration and thereafter decreased slowly. At Tmax, the unchanged menaquinone-4 in the plasma corresponded to 79.6% of the total radioactivity.
    2. Within 168 hours, 2.3 and 78.1% of the radioa ctivity was excreted into the urine and feces, respectively. Unchanged menaquinone-4 corresponded to 28.5% of the radioactivity in the feces excreted within 24 hours.
    3. The liver (33164.0 ng eq./g) and spleen (12542.2 ng eq./g) showed much higher concentrations of radioactivity than the other tissues and plasma (2994.5 ng eq./ml) at 1.5 hours after administration. The concentration in bile (109392.1 ng eq./ml) was also high, suggesting that the menaquinone-4 was immediately excreted into the bile. The elimination of radioactivity from tissues was relatively slow compared to that from plasma. In bone tissues, the target organ of the drug, the marrow (1424.9 ng eq./g) and cancellous tissue (2465.7 ng eq./g) of thighbone and the marrow (3533.4 ng eq./g) of ribs showed levels as high as the plasma concentrations at 1.5 hours and were 2 to 3 times higher than that of the plasma at 24 hours after dosing.
    4. The unchanged menaquinone-4 was the major form present in the plasma, liver, kidney, spleen, adrenal, adipose and cancellous tissue of thighbone at 1.5 hours after administration. The known metabolites, ω-COOH, K acid I and K acid II, were found in these tissues at 1.5 hours. In the adipose and cancellous tissue of thighbone, the unchanged menaquinone-4 was the major form up to 168 hours, while the relative amount of metabolites increased by 24 hours in the other tissues. Polar metabolites were found in the urine excreted within 24 hours and bile at 1.5 and 24 hours after administration. The unchanged menaquinone-4 was mainly found in the feces excreted within 24 hours.
    5. The levels of radioactivity in the marrow and cancellous tissue of thighbone and the marrow of ribs at 1.5 and 24 hours after dosing (1.5 hours: 3.3−8.0×10-6 M, 24 hours: 1.9−3.1×10-6 M) were comparable to the pharmacologically effective concentrations of menaquinone-4 (10-6−10-5 M) in in vitro studies on bone formation. This finding suggests that menaquinone-4 distributes sufficiently into bone tissues after a single oral administration in dogs, and can be expected to maintain pharmacologically effective concentrations by repeated administration as a therapeutic agent for osteoporosis.
  • Yoshihisa SANO, Kyoichi TADANO, Kiyomi KIKUCHI, Kazuhiro KANEKO, Terua ...
    1997 年 12 巻 1 号 p. 58-67
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    [14C]menaquinone-4, a therapeutic agent for osteoporosis, was administered orally to male dogs at a dose of 4 mg/kg once a day for seven days, and the absorption, distribution, metabolism and excretion were investigated.
    1. The mean plasma concentration of radioactivity reached a maximum level at 1.5 hours after the 1st administration and thereafter decreased slowly. The concentrations at 1.5, 4 and 24 hours after each dose increased daily and approached a steady state by the 7th (final) dose, whereas constant plasma concentrations of unchanged menaquinone-4 were observed during repeated administration. The concentrations of radioactivity in erythrocytes increased during repeated administration and had not reached a steady state by the 7th dose.
    2. The concentrations of radioactivity in the bile, liver, adipose, gall bladder and spleen at 1.5 hours after the final dose were 1.0, 0.9, 10.1, 0.6 and 1.2 fold, respectively, and were greater than those after a single dose. Radioactivity was highly accumulated in adipose tissues. In bone tissues, the target organ of the drug, the marrow and cancellous tissue of thighbone and the marrow of ribs showed higher concentrations than plasma levels at 1.5 hours, and were 3.7, 2.6 and 2.7 fold higher, respectively, than those after a single dose.
    3. In urine and feces, 2.4 and 84.0% of the dosed radioactivity was excreted within 168 hours after the 7th dose, respectively. Unrecovered radioactivity was present in the adipose and other tissues at 168 hours.
    4. The metabolic profile of [14C]menaquinone-4 after repeated administration was similar to that after single administration. The unchanged menaquinone-4 was the major form present in the plasma, liver, kidney, spleen, adrenal, adipose and cancellous tissue of thighbone at 1.5 hours and in feces excreted within 24 hours after the 7th dose. In the adipose and cancellous tissue of thighbone, the unchanged menaquinone-4 was the major form up to 168 hours, while the relative amounts of metabolites increased by 24 hours in the other tissues.
    5. The levels of radioactivity in the marrow and cancellous tissue of thighbone and the marrow of ribs increased with repeated administration, and in the end were comparable to the pharmacologically effective concentrations of menaquinone-4 (10-6−10-5 M) observed in n vitroi studies on bone formation. It is, therefore, expected that repeated administration of menaquinone-4 may contribute to the pharmacological action of the drug as a treatment for osteoporosis.
  • 田中 由夫, 野口 英世, 仮家 公夫
    1997 年 12 巻 1 号 p. 68-75
    発行日: 1997/02/28
    公開日: 2007/03/29
    ジャーナル フリー
    Sex difference in the elimination of drugs can be due to either a difference in excretion or in metabolism. Sex differences in drug metabolism are well known and occur in both phase I and II metabolism, while the situation with excretion, especially renal excretion, is unclear.
    Zenarestat, [3-(4-bromo-2-fluorobenzyl)-7-chloro-2, 4-dioxo-1, 2, 3, 4-tetrahydroquinazolin-1-yl] acetic acid is an aldose reductase inhibitor. Rat shows a marked sex difference in the excretion of 14C-zenarestat: only 1 % of the dose was excreted in the urine of males, about 45% of the dose was excreted in the urine of females. 14C in the urine of female rats was almost entirely unchanged drug. Renal clearance experiments, and inhibition of urinary excretion by probenecid, indicated that female rats may possess an active secretory mechanism which is lacking or relatively inactive in male rats.
    Castration of male rats at 22 days of age abolished th e adult sex difference in urinary excretion of zenarestat, while castration at 5 weeks of age produced urinary excretion of the drug about half that in females. Ovariectomy of females at 22 days or 5 weeks of age had no effect on the urinary excretion of zenarestat. Treatment of male and female gonadectomized rats with testosterone resulted in the urinary excretion of zenarestat characteristic of intact adult male rats.
    Hypophysectomized male rats and normal female rats has similar urinary excretion of zenarestat which was much greater than that of normal male rats. Treatment of male and female hypophysectomized rats with testosterone resulted in the urinary excretion of zenarestat characteristic of intact adult male rats. Urinary secretion of zenarestat in rats is independent of pituitary hormone and is suppressed only by androgen.
    Urinary excretion of zenarestat scarcely differed between 3-week-old male and female rats; it decreased in males from 4 weeks of age, but in females urinary excretion of the drug was essentially constant during ageing.
    Mice show a sex difference in the excretion of zenarestat similar to that seen in rats, but dogs and humans show no significant sex difference. Female rats and mice, and both sexes of dogs and humans, appear to possess an active secretory mechanism in the renal excretion of zenarestat, which is lacking or relatively inactive in male rats and mice.
    The effect of acute ( ?? 1 week) and chronic ( ?? 3 weeks) streptozocin induced diabetes on the pharmacokinetics of zenarestat was studied in male and female rats. In male acute and chronic diabetic rats, the urinary excretion increased compared with the control after the dose with 14C-zenarestat. It did not change in female acute diabetic rats and decreased in female chronic diabetic rats compared with the control. Renal clearance experiments suggested that the decrease in urinary excretion in female chronic diabetic rats is due to a decrease in active secretion. The increase in the urinary excretion in male rats was probably due to a decrease in testostereone levels in the diabetic state.
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