著者

森鼻 健史 金子 明寛 富田 文貞 諏訪 俊男 河野 喜郎 小林 寅哲

出版者

公益財団法人 日本感染症医薬品協会

雑誌

The Japanese Journal of Antibiotics (ISSN:03682781)

巻号頁・発行日

vol.42, no.4, pp.973-982, 1989-04-25 (Released:2013-05-17)

参考文献数

15

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新規マクロライド系抗生物質Clarithromycin (TE-031, A-56268) はラット顎下腺におけるミクロオートラジオゲラフィーによる分布状態の検討では腺房, 導管部共に良好な14C-TE-031の集積がみられた。健康成人男子ボランティア3名によるTE-031 300mg単回投与の血清中, 及び唾液中移行濃度は平均値でそれぞれCmax1.49μg/ml, 1.93μg/ml. Tmax2.91時間, 2.66時間, T1/2 6.31時間, 4.15時間, AUC18.58μg・hr/ml.17.70μg・hr/mlである。又, 同症例から得られた唾液中細菌叢は本剤の唾液中濃度の上昇に伴い, 総細菌数は減少したが12時問後には回復した。又, 経過中菌の耐性化はみられなかつた。以上本剤は個体差はあるものの, 血清中を上回る唾液中移行濃度を示し, 唾液によるTherapeutic drug monitoring (TDM) も可能な薬剤と考える。又, 本剤によると思われる一過性の唾液細菌叢の減少はみられるものの早期に回復し, 単回投与では耐性菌の出現もなく短期投与では口腔正常細菌叢への影響の少ない薬剤と考える。Clarithromycin (TE-031, A-56268) は大正製薬株式会社総合研究所でErythromycin (以下, EM) から合成された新規マクロライド系抗生物質であり, 良好な血中及び組織移行性を示すことが知られている。臨床的にも急性歯性感染症に対し, EMの1/4~1/3量である1日300~400mg投与で約80%の有効率が得られている1)。我々は, 本剤が唾液中への移行性が良いとされていることから1), 顎下腺組織への移行性について, ラットに14C-TE-031を投与後の移行分布をミクロオートラジオグラフィーにて検討し, 又, 3名の健康男子ボランティアに対し本剤300mgを食前投与し, 経時的に血清中及び唾液中濃度を測定すると共に, 唾液中細菌叢への影響を調べた。

著者

大村 貞文 森本 繁夫 長手 尊俊 安達 孝 河野 喜郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.112, no.9, pp.593-614, 1992-09-25 (Released:2008-05-30)

参考文献数

60

被引用文献数

7 18

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A series of O-alkylated derivatives of erythromycin (EM) has been prepared and their biological properties were evaluated. Among them, clarithromycin (CAM, 6-O-methylerythromycin) exhibits most potent in vitro and in vivo antibacterial activities, higher acid-stability than EM and favorable pharmacokinetic properties as an antibiotic. CAM was originally synthesized via methylation of 2'-O, 3'-N-bis (benzyloxycarbonyl)-N-demethylerythromycin in low yield, because of the less selectivity of 6-O-methylation. The selective 6-O-methylation was achieved using the erythromycin 9-oxime derivative as a key intermediate. By the further investigation on the protective groups of 9-oxime and desosamine moiety, the production process of CAM on an industrial scale has been established via methylation of 2', 4"-O-bis (trimethylsilyl) erythromycin 9-[O-(1-isopropoxycyclohexyl) oxime] in more than 45% overall yield. CAM has the same antibacterial spectra as EM and is active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, Mycoplasma and Chlamydia. The activity of CAM against clinical isolates was 1 to 16 times higher than that of EM. The efficacies of CAM were 6 to 15 times superior to those of EM against systemic infections due to Gram-positive bacteria in mice. CAM also showed more potent therapeutic efficacies than EM against respiratory tract infections caused by S. pneumoniae and H. influenzae. CAM was well absorbed after oral administration, and its distribution to various tissues was significantly higher than that of EM in animals. The level of CAM in the lung was extremely high, which accounted 69 times that of EM. CAM was found to be distributed predominantly in the alveolar wall, especially in the alveolar epithelial cells, by microautoradiography. After oral administration in human, the serum level and urinary excretion of CAM were 5 and 20 times higher than those of EM, respectively. The major and active metabolite of CAM in human, (14R)-14-hydroxyclarithromycin, existed in significant quantity in the serum and urine, suggesting that the metabolite contributes to the excellent clinical efficacy of CAM. This paper describes the synthesis, structure-activity relationships, antibacterial activities, metabolism and clinical efficacies of CAM, a new macrolide antibiotic.