Jarukamjorn K, Thalhammer T, Gollackner B, Pittenauer E, Jäger W
Institute of Pharmaceutical Chemistry, University of Vienna, Austria.
J Pharm Pharmacol. 1998 May;50(5):515-9. doi: 10.1111/j.2042-7158.1998.tb06193.x.
Roxithromycin is a macrolide antibiotic with high clinical potency. N-Demethylation is considered to be one of the main pathways of roxithromycin metabolism in rats. We have studied the hepatic metabolism of roxithromycin in the isolated perfused rat liver. After addition of roxithromycin (30 microM) to the perfusion medium the parent compound and one major metabolite were detected in bile by high-performance liquid chromatography. The metabolite was identified as monodesmethylated roxithromycin by mass spectrometric analysis. Onset of biliary excretion of native roxithromycin was fast, reaching a maximum (130.52 +/- 43.88 pmol g(-1) min(-1)) after only 10 min, whereas excretion of the metabolite was delayed (maximum 75.83 +/- 11.92 pmol g(-1) min(-1) at 30 min). The cumulative excretion of roxithromycin and its metabolite into bile during the 60 min of application amounted to only 1.09 +/- 0.30 and 0.64 +/- 0.22% of the roxithromycin cleared from the perfusate during the same time. The liver content was 0.48 micromol (g liver)(-1), indicating high retention within the organ. No release of the metabolite into the perfusate was detected. In conclusion, this study has demonstrated the importance of phase-I metabolism for the biliary excretion of roxithromycin in rat liver. These findings might be predictive of roxithromycin biotransformation and biliary excretion in man.
罗红霉素是一种具有高临床效力的大环内酯类抗生素。N - 去甲基化被认为是罗红霉素在大鼠体内代谢的主要途径之一。我们研究了罗红霉素在离体灌注大鼠肝脏中的肝代谢情况。向灌注培养基中加入罗红霉素（30微摩尔）后，通过高效液相色谱法在胆汁中检测到母体化合物和一种主要代谢物。通过质谱分析将该代谢物鉴定为单去甲基罗红霉素。天然罗红霉素的胆汁排泄开始迅速，仅10分钟后就达到最大值（130.52±43.88皮摩尔·克⁻¹·分钟⁻¹），而代谢物的排泄则延迟（30分钟时最大值为75.83±11.92皮摩尔·克⁻¹·分钟⁻¹）。在给药60分钟期间，罗红霉素及其代谢物进入胆汁的累积排泄量仅占同期从灌注液中清除的罗红霉素的1.09±0.30%和0.64±0.22%。肝脏含量为0.48微摩尔·（克肝脏）⁻¹，表明在器官内有高保留。未检测到代谢物释放到灌注液中。总之，本研究证明了I相代谢对罗红霉素在大鼠肝脏中胆汁排泄的重要性。这些发现可能预测罗红霉素在人体内的生物转化和胆汁排泄。
