Affiliation:
1. Service de Pharmacie Clinique, Centre Hospitalier Universitaire Bicha-Claude Bernard, Paris, France.
Abstract
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference40 articles.
1. (~)-S-[3H]CGP-12177 and its use to determine the rate constants of unlabeled ~-adrenergic antagonists;Affolter H.;Proc. Natl. Acad. Sci. USA,1985
2. Efflux of bis-carboxyethyl-carboxyfluorescein (BCECF) by a novel ATP-dependent transport mechanism in epithelial cells;Allen C. N.;Biochem. Biophys. Res. Commun.,1990
3. Beermann D. H. Scholl W. Wingender D. Forster E. Beutler and W. R. Kukovetz. 1986. Metabolism of ciprofloxacin in man p. 141-149. In H. C. Neu and H. Weuta (ed.) Proceedings of the 1st International Ciprofloxacin Workshop. Excerpta Medica Amsterdam.
4. Pefloxacin clinical pharmacokinetics;Bressolle F.;Clin. Pharmacokinet.,1994
5. The three multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal human tissues;Croop J. M.;Mol. Cell. Biol.,1989
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