Rabbaa L, Dautrey S, Colas-Linhart N, Carbon C, Farinotti R
Service de Pharmacie Clinique, Centre Hospitalier Universitaire Bicha-Claude Bernard, Paris, France.
Antimicrob Agents Chemother. 1996 Sep;40(9):2126-30. doi: 10.1128/AAC.40.9.2126.
The aim of this work was to examine the mechanism involved in intestinal elimination of the two optical isomers of ofloxacin in the rat. An intestinal segment was isolated in situ and perfused with saline, while drug solution was administered via the carotid artery. Blood samples and intestinal effluents were collected and analyzed by a high-performance liquid chromatography method. We observed saturable and stereoselective intestinal elimination of the ofloxacin enantiomers. The elimination process favored the R-(+) form of the molecule. After a parenteral dose of 20 mg of racemic ofloxacin per kg of body weight, intestinal clearances were 0.23 +/- 0.03 versus 0.30 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively. Ciprofloxacin and pefloxacin interfered with ofloxacin elimination and significantly reduced the intestinal clearance of S-(-)- and R-(+)-ofloxacin. With concomitant ciprofloxacin, intestinal clearances became 0.13 +/- 0.02 versus 0.17 +/- 0.03 ml/min and 0.14 +/- 0.01 versus 0.19 +/- 0.05 ml/min with pefloxacin for S-(-)- and R-(+)-ofloxacin, respectively. Those findings argue for the presence of a common transport system in the rat intestine with variable affinities for fluoroquinolones. In addition, verapamil and quinidine, two P-glycoprotein blockers, significantly reduced the intestinal elimination of both ofloxacin isomers (with concomitant verapamil, intestinal clearances were 0.12 +/- 0.02 versus 0.18 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively, while with concomitant quinidine, values were 0.18 +/- 0.01 versus 0.23 +/- 0.01 ml/min without modifying their areas under the concentration-time curve in serum. Similar results were found with another fluoroquinolone, ciprofloxacin, in previous work. P-glycoprotein appears to be involved in the intestinal elimination of fluoroquinolones in rats. The characterization of fluoroquinolone intestinal elimination has significant clinical relevance for the better evaluation of the influence of this secretory pathway on antibiotic efficacy and selection of resistant bacteria within the intestinal flora.
本研究旨在探讨大鼠肠道对氧氟沙星两种光学异构体的消除机制。原位分离一段肠段并用生理盐水灌注，同时经颈动脉给予药物溶液。采集血样和肠流出液，采用高效液相色谱法进行分析。我们观察到氧氟沙星对映体在肠道的消除具有饱和性和立体选择性。消除过程有利于分子的R-(+)形式。静脉注射每千克体重20毫克消旋氧氟沙星后，S-(-)-和R-(+)-氧氟沙星的肠道清除率分别为0.23±0.03和0.30±0.03毫升/分钟。环丙沙星和培氟沙星干扰氧氟沙星的消除，并显著降低S-(-)-和R-(+)-氧氟沙星的肠道清除率。同时给予环丙沙星时，S-(-)-和R-(+)-氧氟沙星的肠道清除率分别变为0.13±0.02和0.17±0.03毫升/分钟；同时给予培氟沙星时，分别变为0.14±0.01和0.19±0.05毫升/分钟。这些发现表明大鼠肠道中存在一种对氟喹诺酮类药物具有不同亲和力的共同转运系统。此外，两种P-糖蛋白阻滞剂维拉帕米和奎尼丁显著降低了两种氧氟沙星异构体的肠道消除（同时给予维拉帕米时，S-(-)-和R-(+)-氧氟沙星的肠道清除率分别为0.12±0.02和0.18±0.03毫升/分钟，而同时给予奎尼丁时，数值分别为0.18±0.01和0.23±0.01毫升/分钟，且未改变其血清浓度-时间曲线下面积）。在先前的研究中，另一种氟喹诺酮类药物环丙沙星也得到了类似的结果。P-糖蛋白似乎参与了大鼠肠道中氟喹诺酮类药物的消除。氟喹诺酮类药物肠道消除的特征对于更好地评估这种分泌途径对抗生素疗效的影响以及肠道菌群中耐药菌的选择具有重要的临床意义。
