Stereoselective Metabolic Disposition of Enantiomers of Ofloxacin in Rats

Okazaki, Osamu; Kurata, Tadashi; Tachizawa, Haruo

doi:10.3109/00498258909042283

Cited by 21 publications

(8 citation statements)

References 16 publications

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“…Ofloxacin is a chiral fluoroquinolone, and its spatial orientation affects antibacterial activity as well as pharmacokinetic properties in rats and humans (9,25,26). After oral administration to rats, Okazaki et al reported a marked difference in the biliary excretion of the two enantiomers (26). Stereoselective ester glucuronidation occurs: S-(Ϫ)-ofloxacin is preferentially metabolized to the glucuronide ester, which is rapidly excreted into the bile.…”

Section: Discussionmentioning

confidence: 99%

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

Rabbaa

Dautrey

Colas-Linhart

et al. 1996

Antimicrob Agents Chemother

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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.

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Section: Discussionmentioning

confidence: 99%

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

Rabbaa

Dautrey

Colas-Linhart

et al. 1996

Antimicrob Agents Chemother

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“…For example, S ‐(‐)‐ofloxacin, a new quinolone antibacterial agent, is 8–128 times more active than R ‐(+)‐ofloxacin against both gram‐positive and gram‐negative bacteria . In addition, conversion of S ‐(‐)‐ofloxacin to the glucuronide in rat liver microsomes is 7‐fold greater than that of R ‐(+)‐ofloxacin . Recently, the histamine H 1 antagonist levocetirizine and the sleep inducer eszopiclone have been approved by the FDA for use as optically active preparations .…”

Section: Introductionmentioning

confidence: 99%

Enantioselective disposition of clenbuterol in rats

Hirosawa

Ishikawa

Ogino

et al. 2013

Biopharm & Drug Disp

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Clenbuterol is a long-acting β2-adrenoceptor agonist and bronchodilator that is used for treatment of asthma, but the desired activities reside almost exclusively in the (-)-R-enantiomer. Here, we examined enantioselectivity in the disposition of clenbuterol following administration of clenbuterol racemate to rats.Concentrations of clenbuterol enantiomers in plasma, urine, and bile were determined by LC-MS/MS assay with a Chirobiotic T column. This method was confirmed to show high sensitivity, specificity, and precision, and clenbuterol enantiomers in 0.1-mL volumes of plasma were precisely quantified at concentrations as low as 0.25 ng/mL. The pharmacokinetic profiles of clenbuterol enantiomers following intravenous and intraduodenal administration of clenbuterol racemate (2 mg/kg) in rats were significantly different. The distribution volume of (-)-R-clenbuterol (9.17 L/kg) was significantly higher than that of (+)-S-clenbuterol (4.14 L/kg). Total body clearance of (-)-R-clenbuterol (13.5 mL/min/kg) was significantly higher than that of the (+)-S-enantiomer (11.5 mL/min/kg). An in-situ absorption study in jejunal loops showed no difference in residual amount between the (-)-R-and (+)-S-enantiomers. Urinary clearance was the same for the two enantiomers, but biliary excretion of (-)-R-clenbuterol was higher than that of the (+)-S-enantiomer. The fractions of free (non-protein-bound) (-)-R-and (+)-S-clenbuterol in rat plasma were 48.8, and 33.1%, respectively. These results indicated that there are differences in distribution and excretion of the clenbuterol enantiomers, and these may be predominantly due to enantioselective protein binding.

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“…In a previous paper, we reported the stereoselective disposition of the enantiomers of OFLX in rats (13), showing that there are marked pharmacokinetic differences between the enantiomers of OFLX caused by stereoselective glucuronidation. The major metabolic pathway of OFLX in rats is glucuronidation of the carboxyl group at the C-3 position of the quinolone ring (20).…”

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Enantioselective disposition of ofloxacin in humans

Okazaki

Kojima

Hakusui

et al. 1991

Antimicrob Agents Chemother

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The enantioselective disposition of ofloxacin (OFLX) was studied in healthy subjects after oral administration of (+/-)-OFLX at a dose of 200 mg. S-(-)-OFLX and R-(+)-OFLX concentrations in serum and urine were measured separately by high-performance liquid chromatography, and various pharmacokinetic parameters were calculated from the data. The ratio of S-(-) to R-(+) enantiomer concentrations in serum showed a increase with time, with S/R ratios of 1.01 at 2 h and 1.31 at 24 h. The terminal elimination half-life of S-(-)-OFLX was 6.9 h, which was significantly greater (P less than 0.05) than that of the R-(+) enantiomer (6.3 h). S-(-)-OFLX also revealed a significantly greater area under the concentration-time curve in serum, mean residence time, and total body clearance than the R-(+) enantiomer did. The renal clearance of S-(-)-OFLX (7.14 liters/h/1.73 m2) was significantly lower than that of the R-(+) enantiomer (7.53 liters/h/1.73 m2). Although the difference in the pharmacokinetic parameters of the enantiomers was small, their disposition in humans was found to be stereoselective. The difference between the enantiomers may be explained by the difference in their renal excretion.

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Stereoselective Metabolic Disposition of Enantiomers of Ofloxacin in Rats

Cited by 21 publications

References 16 publications

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

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

Enantioselective disposition of clenbuterol in rats

Enantioselective disposition of ofloxacin in humans

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