[Relationship between the chemical structure of O-methyl erythromycin derivatives and their affinity to the lung].
Clarithromycin (CAM) was synthesized by selective methylation of the C-6-hydroxy group of erythromycin (EM), which had a high affinity to the lung. In the present study, the relationship between the chemical structure of derivatives of O-methyl group for the hydroxy group at 6, 11, 12 and 4"-position of the EM and their affinity to the lung was investigated. When each O-methyl EM derivatives was injected into the external jugular vein in rats, the lung levels were in decreasing order, 6,11,12,4"-OCH3 > 6,12-OCH3 > 6,11,4"-OCH3 > 6,4"-OCH3 > 6,11-OCH3 > 6-OCH3 > 11-OCH3 > EM. There was not a correlation between the lung affinity and dissociation constant (pKa). It was found that substitution of a O-methyl group for the hydroxy group at each position afforded both the affinity to the lung and the lipophilicity. However, the levels of the increase were inconsistent for each substitution position. In the case of 6 and 12-position afforded higher affinity than that for 11 and 4"-position. A study of the effect of EM derivatives on the [14C]EM and [14C]CAM uptake process into the isolated lung cells was carried. The uptake of [14C]EM was not influenced by EM, CAM and 6,11,12,4"-OCH3. On the other hand, the uptake of [14C]CAM was significantly inhibited in the presence of derivatives which had a O-methyl substitution at position 6, but was not influenced by an O-acethyl substitution. These findings suggest that CAM is transported via carrier-mediated system in the lung cells, which has a selective recognition the O-methyl group at position 6. In addition, the uptake of [14C]CAM was further inhibited by the derivatives with O-methyl group at position 12.
Yoshida
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H
Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co., Ltd.
Furuta
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T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004917:Erythromycin