Laboratory of Drug Information Analytics, Faculty of Pharmacy & Pharmaceutical Sciences, Fukuyama University, Hiroshima International University, Hiroshima, Japan.
Department of Pharmacy, Chugoku-Rosai Hospital, Hiroshima International University, Hiroshima, Japan.
Pharmazie. 2020 Nov 1;75(11):554-558. doi: 10.1691/ph.2020.0601.
A prodrug of levofloxacin (LVFX), cilexetil ester of LVFX (LVFX-CLX), was synthesized to examine whether the prodrug can avoid chelate formation with metal cations in the gastrointestinal tract. LVFX-CLX exhibited a 10-times higher partition coefficient than LVFX. In vitro, LVFX was precipitated by 76.1% in the presence of a 10-times higher concentration of aluminium chloride (Al), but LVFX-CLX was not. LVFX-CLX was rapidly hydrolyzed enzymatically by rat plasma, intestinal mucosal and liver homogenates at 37 °C, but not by pancreatic enzymes and luminal fluid. The minimum inhibitory concentration values of LVFX-CLX against and were far higher than that of LVFX. In rats, area under the plasma concentration-time curve from zero to 4 h (AUC) of LVFX after oral administration of LVFX-CLX was 1.34-fold higher than that after LVFX, though it did not reach significance level. Co-administration of Al with LVFX and LVFX-CLX in rats decreased AUC of plasma LVFX by 75% and 60%, respectively, however, the AUC of plasma LVFX after co-administration of LVFX-CLX and Al was 2.2-times higher than that after co-administration of LVFX and Al. These results suggested that the use of LVFX-CLX may reduce the modulation of intestinal microflora caused by LVFX and the suppressive effect of Al on intestinal absorption of LVFX.
左氧氟沙星前药（LVFX）的西司他丁酯（LVFX-CLX）被合成，以检验前药是否能避免在胃肠道中与金属阳离子形成螯合物。LVFX-CLX 的分配系数比 LVFX 高 10 倍。在体外，当铝浓度（Al）增加 10 倍时，LVFX 有 76.1%沉淀，但 LVFX-CLX 没有。LVFX-CLX 在 37°C 下可被大鼠血浆、肠黏膜和肝匀浆快速酶解，但不能被胰酶和腔液酶解。LVFX-CLX 对 和 的最小抑菌浓度值远高于 LVFX。在大鼠中，口服 LVFX-CLX 后 LVFX 的血浆浓度-时间曲线下面积（AUC）比 LVFX 高 1.34 倍，但未达到显著水平。在大鼠中，LVFX 和 LVFX-CLX 与 Al 共同给药后，血浆中 LVFX 的 AUC 分别降低了 75%和 60%，然而，LVFX-CLX 和 Al 共同给药后血浆中 LVFX 的 AUC 比 LVFX 和 Al 共同给药后高 2.2 倍。这些结果表明，使用 LVFX-CLX 可能会减少 LVFX 对肠道微生物群的调制作用和 Al 对 LVFX 肠道吸收的抑制作用。
