CHEMOTHERAPY JUNE 1988 ( })-1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-l-piperaziny1) 4-oxo-3-quinolinecarboxylic acid hydrochloride Fig. 1. Chemica

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1 CHEMOTHERAPY JUNE 1988 ( })-1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-l-piperaziny1) 4-oxo-3-quinolinecarboxylic acid hydrochloride Fig. 1. Chemical structure of NY-198

2 VOL CHEMOTHERAPY Mouse (n=6) Rat (n=5) Dog (n=4) Fig. 2. Serum concentrations of NY-198 after oral administration to mice, rats and dogs at a dose of 20 mg/ kg (mean+s. E.).

3 CHEMOTHERAPY JUNE 1988 Fig. 3. Serum concentrations of NY-198 after oral administration to rats at different doses (mean+s. E.). Fig. 4. Serum concentrations of NY-198 after oral and intravenous administration to rats at a dose of 20 mg/kg (mean+s. E.).

4 Table 1. Urinary concentrations of NY-198 after oral administration at a dose of 20 mg/kg ND: not detected (0.39 Đg/ml>) Table 2. Urinary excretion of NY-198 after oral administration at a dose of 20 mg/kg NT: not tested Table 3. Tissue concentrations of NY-198 after oral administration to rats at a dose of 20 mg/kg AUC: area under the curve calculated by trapezoidal rule Fig. 5. Serum concentrations of NY-198 after oral and intravenous administration to dogs at a dose of 5 mg/kg (mean } S. E.).

5 136 CHEMOTHERAPY JUNE Table 4. Concentration used of NY in urine for TLC-bioautography と血 清 中濃 度 はマ ウ ス,ラ ッ トで は投 与 後15分,イ ヌで は1時 間 に ピ ー ク に達 し,最 高 血 清 中濃 度 は ラ ッ トとイ ヌが 同程 度 で マ ウス が 最 も低 い 濃 度 を 示 し,約1/2で Fig. 6. Tissue concentrations of NY-198 after oral administration to rats at a dose of 20 mg/kg (mean). っ た AUCは あ イ ヌ が最 も高 く,続 い て ラ ッ ト,マ ウスの 順 で あ った また,静 脈 内 投 与 との比 較 で はAuc比(p.o./i.v)は ラ ッ トで0.85,イ ヌ で0,94と 経 口 吸収 が非 常 に優 れ てい る こ とが示 唆 さ れ た 組 織 へ の移 行 性 につ い て も,ラ ッ トで は血 清 と同様 に 経 口投 与 後15 30分 で ピー ク に達 した 各 組 織 の最 高濃 度 お よびAUC(0 6h)は 血 清 の そ れ と比 較 して,肺 で 0,70倍 お よび0.63倍 とや や 低 か っ た 他 は 各 々 倍 お よび 倍 高 く,組 織 移 行 性に優 れ た結 果 を示 した 中 で も腎 が最 も高 い値 を示 し,尿 中排 泄 に お い て も,ラ ッ トで69.9%,イ OFLXに ヌ で53,8%とNFL瓦 比 べ 高 い値 を示 した3) また,尿 のバ イ オ オ ー トグ ラみ よ り,ラ ッ ト,イ ヌお よび サル の い ず れ にお い て も尿 中 に は未 変化 体 の NY198以 外 に抗 菌 活性 を有 す る代 謝 物 が な く,生 体 内 中で抗 菌活 性 を示 して い る物 質 は大 部 分 が 未 変 化 体 で あ る こ と が 明 らか とな った な お,既 に我 々 は ヒ トにお い て も同様 の こ と を報 告4} Fig. 7. TLC-bioautograms of urine collected after oral administration of NY-198 to rats, dogs and monkeys at a dose of 20 mg/kg. Absorbent : DC-Alufolien Kieseigei 60F254 (Merck) Sample amount : 1 µl Test organism. E. coli NIHJ JC-2 Solvent : dioxane-28% ammonia water (3 : 2) して い る 以 上 の 結果 よ り,NY-198がin vitro抗 はNFLXお よびOFLXと 菌 力 にお い て 同等 で も,種 々め 実 験 的感 染 モ デ ル に対 して経 口 投 与 で優 れ た効 果 を示 す 理 由 と して. 経 口 吸収 が 良 好 な こ と,組 織 移 行 性 に優 れて い る こ と, 代 謝 され に くい こ とが示 唆 され 経 口剤 と して優 れ た治 療 効 果 が期 待 で きる化 合 物 で あ る と考 え られ た 本 試 験 は 昭 和59年8月 施 した か ら昭 和62年1月 の期 間に実

6 VOL.36 S-2 CHEMOTHERAPY DISPOSITION AND METABOLISM OF NY-198 I. BIOASSAY STUDY OF ABSORPTION, DISTRIBUTION AND EXCRETION IN VARIOUS ANIMALS EIICHI OKEZAKI, KOHICHI OHMICHI, SHOJI KOIICE, YOSHIE TAKAHASHI and EIICHI MAKINO Central Research Laboratory, Hokuriku Seiyaku Co., Ltd., Fukui TETSUYA TERASAKI, AKIRA TSUJI Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa Absorption, distribution and excretion of NY-198, a new pyridonecarboxylic acid derivative, were examined by bioassay in mice, rats and dogs after a single oral and intravenous administration. 1. The peak serum concentration (Cmax) of NY-198 after oral administration to mice, rats and dogs at a dose of 20mg/kg were 5.30, 9.73 and 9.64 Đg/ml, namely, Cmax in mice was lower than in rats and dogs. Ratios of area under the curve (AUC) of oral to intravenous administration (p.o./i.v.) to rats (20 mg/kg) and dogs (5 mg/kg) were 0.85 and NY-198 showed excellent oral absorbability in rats and dogs. 2. Cmax of NY-198 after oral administration to rats at a dose of 10, 20 and 40 mg/kg was 5.90, 9.73 and 22.46/4/ ml. Their AUC's were 11.4, 22.6 and 55.1 pg/ml, respectively. Cmax and AUC increased dose-dependently. 3. The urinary excretion rate of NY-198 after oral administration of 20 mg/kg was 69.9% within 24 h in rats and 53.8% within 72 h in dogs. Urinary recovery of NY-198 was excellent. 4. After oral administration to rats, NY-198 was distributed in kidney, liver, prostate and skeletal muscle at higher than serum levels, but in lung it was slightly lower. 5. Antibacterial metabolites in urine of rat, dog and monkey after oral administration were examined by TLC-bioautography and no active metabolites were detected. These results indicate that NY-198 is excellently absorbed after oral administration, distributed in most tissues of the body at high concentrations and that it is not metabolized, but excreted unchanged mainly into urine.

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