¹²⁵I-KW-2228のラットにおける単回静脈内および皮下投与後の血漿中濃度推移，分布，代謝および排泄について検討した．各試料について，総放射能以外にトリクロロ酢酸(TCA)分画により，低分子代謝物および¹²⁵Iを除いたTCA不溶性放射能も併せて測定した．
1．¹²⁵I-KW-2228を静脈内投与後，総放射能およびTCA不溶性放射能は血漿中より二相性に消失した．TCA不溶性放射能は総放射能に比較して速やかに消失し，消失相の半減期は総放射能の約1/2であった．皮下投与においては，総放射能およびTCA不溶性放射能は投与後2時間にC_maxを示した．このときのTCA不溶性放射能の割合は高く，血漿中へ未変化体の形で吸収されたものと考えられた．C_max以降の消失は静脈内投与同様，TCA不溶性放射能は総放射能に比較し，速やかであった．SDS-PAGEの結果，血漿中放射能のうち抗体結合性のものは，いずれの投与経路においてもほとんどがKW-2228そのものと考えられた．
2．いずれの投与経路においても，TCA不溶性放射能は腎臓に最も高濃度に分布し，腎臓は¹²⁵I-KW-2228の主代謝組織と思われた．他の組織においては，静脈内投与と皮下投与時の分布に差が認められた．標的臓器である骨髄においては，皮下投与時に放射能の消失が遅く，白血球増多効果が皮下投与の方が高いことの一因と思われた．甲状腺，胃および皮膚に高濃度の放射能が分布したが，これは¹²⁵I-KW-2228が分解し，遊離した¹²⁵Iによるものと考えられた．
3．¹²⁵I-KW-2228の主排泄経路は尿であり，投与経路による差ば認められなかった．尿中放射能のほとんどは低分子の代謝物または遊離の¹²⁵Iと考えられた．

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Plasma concentration, distribution, metabolism and excretion of KW-2228 following multiple subcutaneous administrations for 10 days were studied in rats using ¹²⁵I-labelled KW-2228 in rats, and the obtained results were compared with those after single administration.
50μg/kg/day of KW-2228 were given to rats for 9 days and ¹²⁵I-KW-2228 on the 10th day only, and then concentration of radioactivity was determined. C_max, AUC, T_1/2 and Cl_tot calculated from TCA-insoluble radioactivity after multiple administrations did not differ from those obtained following single administration. The highest concentration of radioactivity was found in the kidney, same as observed by single administration.
The distribution and elimination in other tissues, including the target organ, bone marrow, were also similar to those after single administration, indicating no cumulative effect, Most of radioactive substances were, like after single administration, excreted in urine, which were TCA-soluble and a low molecular weight metabolites such as ¹²⁵I.
These results show that none of plasma pharmacokinetics, distribution, metabolism and excretion differ from those obtained after single administration and that the pharmacokinetics of KW-2228 is not affected by multiple subcutaneous administration.

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KW-2228のラットにおける血漿中動態について検討した．血漿中濃度の測定ぱELISA法により行った．
1．KW-2228をラットに5～150μg/kg静脈内投与したとき，いずれの投与量においても，KW-2228は血漿中より二相性に消失した．しかし，その消失半減期は5μg/kgの0.79時間から，150μg/kgの2.16時間と投与量に依存して延長し，KW-2228の消失に飽和過程の関与が考えられた，この血漿中濃度推移は，Michaelis-Menten型消失を含むモデルに良く適合し，Michaelis定数は2.3ng/ml，最大消失速度は19.27ng/ml/hrであった．
2．KW-2228をラットに15～150μg/kg皮下投与したとき，KW-2228は投与後1.5～2.0時間にC_maxを示し，その後一相性の消失を示した．50および150μg/kgでは半減期は約1.5時間であった．C_max．およびAUCは，投与量に対して非線形性を示した．
3．KW-2228を50μg/kg1日1回10日間反復皮下投与したとき，反復投与後では6時間以降，単回投与に比較して低い血漿中濃度を示し，半減期の短縮も認められた．
4．rhG-CSFを50μg/kg静脈内および皮下投与後の血漿中濃度推移をKW-2228と比較したが，大きな差は認められなかった．

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KW-2228およびrhG-CSFを，10μg/kgカニクイザルに静脈内および皮下投与時の血漿中動態，白血球数増多作用について検討した．また，反復皮下投与についても検討した．
1．KW-2228を単回静脈内投与により，末梢血白血球数(WBC)の著明な増加が認められた．WBCは，投与後12時間に最高値，投与前の約2倍を示し，24時間後においてほぼ投与前値まで回復した．一方，単回皮下投与においては投与後12時間に最大に達し，投与前値の約4倍を示した．反復皮下投与では投与を重ねるに従い，WBCは上昇し，10日目の12時間値では初回投与前の約6倍を示した．白血球の上昇は主に分葉核好中球の上昇によるものであった．rhG-CSFについても同様なWBC増多作用が認められ，KW-2228と有意な差は認められなかった．また，赤血球数および血小板数には大きな変動は認められなかった．
2．血漿中KW-2228は，静脈内投与後二相性に消失し，このときの半減期は0.43±0.09時間(%alpha;)，1.34±0.35時間(β)であった．rhG-CSFもKW-2228と同様に二相性の消失パターンを示したが，αおよびβ相の半減期はそれぞれ0.40±0.04，1.11±0.05時間であり，KW-2228に比較し短いものであった．
3，血漿中KW-2228およびrhG-CSFは皮下投与後，共に2時間にC_max13.20±3.76，8.37±2.81ng/mlを示し，その後一相性に消失した．このときKW-2228濃度は2，6，8，10，12時間においてrhG-CSF濃度に比べ有意に高く，1.5～2倍の血漿中濃度を示した．KW-2228およびrhG-CSFの消失相の半減期はそれぞれ2.03±0.64，1.34±0.49時間であった．
10回反復投与後の血漿中KW-2228のC_maxは，初回投与に比べ約2/5に減少し，半減期も約2/3と短いものであった．また，AUCは初回投与の約1/4であった．rhG-CSFについてもほぼ同じ傾向であった．反復投与後の血漿中濃度においては，KW-2228とrhG-CSFの間に差は認められなかった．

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It is known that SN-38, a main metabolite of the novel camptothecin derivative CPT-11, shows a more potent anti-proliferative effect than CPT-11, in vitro. Therefore, it is presumed that SN-38 greatly influences the antitumor effect of CPT-11. In this study, we examined the generation of SN-38 from CPT-11 by plasma and tissue homogenates from the rat, dog, and man.
1. In the rat, the plasma, followed by the intestine, showed the highest activity in the generation of SN-38, and activity was also detected in the lung, liver, and kidney.
2. In the dog, the liver showed the highest sustained activity, but little activity was detected in the plasma and intestine.
3. In human subjects, almost the same activity was initially detected in the liver and intestine, but only the liver showed sustained activity. Plasma possessed marginal activity.
4. Comparison of the rat, the dog, and man showed remarkable species differences in the activity of the plasma, but not in that of the liver.
5. Among rat liver cell fractions, microsomes showed the highest activity, and the activity was also detected in the mitochondria. However, the activity of lysosomes was low.
6. The microsomal fraction of rat liver and tissue homogenates (liver, intestine, kidney, and lung) prepared from the rat showed almost equal Michaelis constants, rang from 20 to 26μM, for the generation of SN-38.
7. The activity of the human liver homogenate was inhibited by more than 80% by DFP (1 × 10^-4M), an inhibitor of serine esterases such as carboxylesterases and cholinesterases. However, 40% inhibition was induced by physostigmine (1 × 10^-4M), an inhibitor of cholinesterases, but none by PCMB (1 × 10^-4M), an inhibitor of arylesterases.

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新規経口用セファロスホリンME1207の生体内活性体であるME1206の腎排泄機構について，ラットは定型腎クリアランス法，ウサギおよびイヌではstop-flow法を用い検討した．
ラットにおけるME1206のERは，ME1206を単独で投与したときは3.64であった．それに対して，iodopyracetを併用し尿細管分泌を阻害したときのERは，0.932であった．これらの結果から，ラットにおいてME1206は，糸球体濾過および尿細管分泌により排泄されると考えられる．
イヌにおいて近位尿細管分泌のマーカーとしてPAHを使用したとき，ME1206のstop-flowパターン上には，分泌あるいは再吸収を示すピークはいずれも認められなかった．ところが，一方，PAHを使用しないとわずかに分泌を示すピークが認められた。これらの結果から，MEI206はイヌにおいて，近位尿細管でわずかに分泌されるものの，主として糸球体濾過により排泄されることが明らかになった．さらに，PAHは有機酸輸送系においてME1206と競合し，そのわずかな分泌を阻害することが示された．
ウサギにおけるME1206のstop-flowハターンには，PAH共存下においても分泌を示す著しいピークが認められた．このピークは，probenecidの投与により完全に消失したことから，ウサギにおいてME1206は，糸球体濾過のみならず近位尿細管分泌により排泄されると考えられる。
以上を総括すると，ME1206の腎排泄機構には，動物種差が認められた．さらに，stop-flow法における尿細管分泌のマーカーには，対象となる薬物と異なる輸送系により分泌されると考えられる物質を用いることが望ましいと考えられる．

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The absorption, distribution, metabolism and excretion of NZ-105 were studied in male rats after a single (10mg/kg) administration of ¹⁴C-NZ-105.
1. Blood levels reached the maximum of 710.8ng eq./ml at 2hr after administration and decreased with half-life of 1.9hr until 11hr.
The absorption of radioactivity was significantly affected by the presence of food in the gastrointestinal tract.
2. The rates of radioactivity excretion in urine and feces within 120hr and bile within 24hr were 2.0, 93.8, and 60.2% of dose, respectively, demonstrating that the major route of excretion was biliary system.
3. The absorption ratio of radioactivity estimated from the sum of biliary and urinary excretions was calculated to be approximately 62%.
4. The radioactivity was high in the gastrointestinal tract and liver, followed by the adrenals. Radioactivity in each tissue was eliminated rapidly, and at 24hr was very low when compared with the maximum value.
5. The unchanged drug in the plasma accounted for 47.7% of total radioactivity at 2hr after administration, suggesting a lower first-pass effect in comparison with other dihydropyridine Ca channel blockers.
6. In plasma, major metabolites of NZ-105 were N-debenzylated compound (DBZ), N-dephenylated compound (DPH), oxidative deaminated compound (AL), AL-corresponding pyridine compound (ALP), unknown metabolite M-1 and M-25. They accounted for 2.5, 5.6, 3.5, 4.9, 3.8 and 14.4% of plasma total radioactivity, respectively, at 2hr after administration.
7. NZ-105 was metabolized by N-debenzylation, N-dephenylation, oxidative deamination, ester hydrolysis and oxidation of 1, 4-dihydropyridine ring to corresponding pyridine.

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Transfer of radioactivities into the fetus and milk after oral administration of ¹⁴C-NZ-105 to pregnant or lactating rats were studied. Absorption, distribution, metabolism and excretion of ¹⁴C-NZ-105 were studied in male rats after repeated oral administration (21 times) at the dose of 10mg, /kg/day.
1. On day 13 and 18 of gestation, the autoradiography revealed that the radioactivity in the fetus was very lower than that in the maternal blood. On day 18 of gestation, the radioactivity in the fetal blood and liver was lower than that in the maternal plasma.
2. Radioactivity level in the milk was similar to that of plasma but it disappeared below detection limit at 48hr after oral administration.
3. Blood levels of radioactivity at 24hr after daily dosing increased with the number of doses. Blood concentration at 24hr after the 21-st dose was 8 times higher than blood concentration at 24hr after the first dosing respectively.
4. After repeated administration, the radioactivities in most of tisuues at 24hr reached the steady state after the 14-th administration.
5. The cumulative excretion of radioactivity in urine and feces accounted for 2.8% and 97.5% of the total dose, respectively, within 120hr after the final administration.
6. The ratio of unchanged drug to its metabolites, measured as a fraction of total radioactivity in the plasma at 2hr after the last dosing was similar to that after the single dose.

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Absorption, metabolism and excretion of ¹⁴C-NZ-105 were studied in male dogs after oral (10mg/kg) administration. Serum protein binding was investigated in the rat, dog and human.
1. Blood levels of radioactivity reached a peak level (564ng eq./ml) at 2hr after administration and then decreased with the half-life of 3. 1hr until 12hr.
2. The excretion of radioactivity in urine and feces within 120hr after oral administration was 3.1% and 98.5% of dose, respectively.
3. The in vitro binding to rat, dog and human serum proteins was 98% or more at 200, 600 and 2000ng/ml. That observed in vivo was 85.8 ?? 89.7% at 0.5, 2 and 6hr after oral administration in rats and 38.5 ?? 45.6% at 2, 4 and 8hr after dosing in dogs.
4. The unchanged drug and oxidatively deaminated compound (AL) were mainly detected in the plasma.

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