Intestinal elimination of ofloxacin enantiomers in the rat: evidence of a carrier-mediated process

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.

Interaction of enrofloxacin with breast cancer resistance protein (BCRP/ABCG2): influence of flavonoids and role in milk secretion in sheep

“…Previous research supported that other fluoroquinolones are subjected to active efflux (Griffiths et al. , 1994; Rabbaa et al. , 1996).…”

Fluoroquinolone disposition: identification of the contribution of renal secretory and reabsorptive drug transporters

“…Later studies in rats confirmed intestinal secretion of parenterally administered ciprofloxacin, fleroxacin, and sparfloxacin and demonstrated that coadministration of ciprofloxacin or pefloxacin significantly reduced the in vivo intestinal clearance of ofloxacin, suggesting a common transport system [40,41]. Subsequent inhibition of in vivo intestinal elimination of ofloxacin by verapamil and quinidine indicated possible involvement of the ABC transporter family, for example, MDR1, in this process [41]. In vitro studies conducted in Caco-2 cell monolayers, a model system for human intestine, demonstrated verapamil-sensitive secretion of grepafloxacin and sparfloxacin, also pointing to ABC transporter involvement in the intestinal secretion of FQs [42,43].…”

“…Therefore, passive diffusion across the GI epithelium and other systemic tissue barrier epithelia should be a negligible component of their [37][38][39]. Later studies in rats confirmed intestinal secretion of parenterally administered ciprofloxacin, fleroxacin, and sparfloxacin and demonstrated that coadministration of ciprofloxacin or pefloxacin significantly reduced the in vivo intestinal clearance of ofloxacin, suggesting a common transport system [40,41]. Subsequent inhibition of in vivo intestinal elimination of ofloxacin by verapamil and quinidine indicated possible involvement of the ABC transporter family, for example, MDR1, in this process [41].…”

Plasma Disposition and Faecal Excretion of Netobimin Metabolites and Enantiospecific Disposition of Albendazole Sulphoxide Produced in Ewes

“…Although interaction between parent ABZ and P-glycoprotein does not occur (Merino et al, 2002), enantioselective transport of ofloxacin and talinolol by P-glycoprotein has been shown in the process of intestinal elimination (Rabbaa et al, 1996;Hanafy et al, 2001). Thus, different intestinal metabolism, interactions and transport of ABZSO could determine the proportions of the enantiomers in faeces and this could explain the different enantiospecific dispositions between plasma and faeces.…”