Pharmacokinetics of gyrase inhibitors, Part 2: Renal and hepatic elimination pathways and drug interactions

Abstract

This article focuses on the relationship of the physicochemical properties of gyrase inhibitors to their hepatic and renal elimination pathways. Luminal fluid concentrations of gyrase inhibitors are affected by an active process and can be inhibited by agents such as probenecid that inhibit tubular secretion of anions. Probenecid may inhibit base transport in the proximal tubule and appears to inhibit base transport as well. Available data suggest that all gyrase inhibitors can be secreted as anions by the proximal tubules. Cimetidine, which is cationic at physiologic pH, inhibits base transport in the proximal tubule and appears to inhibit base transport of gyrase inhibitors. Reabsorption also affects tubular concentrations. Models that describe the effects of urinary flow and pH are discussed. The N4'-methylated derivatives are the most lipophilic, and addition or removal of the methyl group can, but does not always, affect reabsorption. The data indicate that all gyrase inhibitors undergo tubular secretion as either acids or bases and that some also are significantly reabsorbed. Hepatic handling and resultant excretion of metabolites are also influenced by the presence or absence of N4'-methylation. A step in the hepatic handling of N4'-methylated gyrase inhibitors that leads to N4'-oxidation has not yet been found in rufloxacin. Rebiotransformation of N4'-oxides was described in liver perfusion experiments. The potential for interaction with theophylline is not identical for all gyrase inhibitors. Enoxacin is the strongest inhibitor of theophylline and caffeine metabolism, followed by tosufloxacin, ciprofloxacin, and pefloxacin. Fleroxacin, ofloxacin, rufloxacin, and sparfloxacin have no or negligible effects. A likely mechanism for this interaction is the inhibition of subsets of the cytochrome P-450 enzyme. Structure activity relationships were established for this interaction. Piperazine ring-cleaved compounds and naphthyridine nuclei were shown to be most active inhibitors of cytochrome P-4501A2. The effect of various substituents was also tested, leading to an equation that predicts inhibition of 3-caffeine demethylation. Piperazine ring-cleaved compounds are more inhibitory than parent compounds, and a nitrogen at position 4 or 7, respectively, reduces or increases inhibitory activity. Data on interactions of rifampin and cyclosporine with gyrase inhibitors are conflicting. Rifampin increases the clearance of fleroxacin but does not change the elimination half-life significantly. Although norfloxacin may interfere with metabolism of the S enantiomer of warfarin, fleroxacin does not affect pharmacokinetics of either the R or S enantiomer or the anticoagulant response.(ABSTRACT TRUNCATED AT 400 WORDS)