Elimination Pathways

The primary route of elimination of most fluoroquinolones is via the kidney [40], the exceptions including pefloxacin, trovafloxacin, grepafloxacin, clinafloxacin, and moxifloxacin, urinary recoveries of which are 10-25% or less [34,37,38,40]. A number of agents are cleared almost exclusively by glomerular filtration and tubular secretion, notably ofloxacin (levofloxacin), lomefloxacin, and, to a lesser extent, fleroxacin. These group members require dosage modification in significant renal impairment and the elderly, leading to more complex dosage recommendations in such patients. In contrast, dose modification for agents such as ciprofloxacin, norfloxacin, and trovafloxacin is required only in patients with creatinine clearances of 20-30 ml/min or less, in whom halving the dose or extending the dosage interval is usually recommended. For pefloxacin, which is extensively metabolized, no adjustments are required. The fluoroquinolones are poorly cleared by both peritoneal dialysis and hemodialysis (<20-30%); pos-themodialysis top-up dosage is not required.

The fluoroquinolones differ markedly in their degree of biotransformation, predominantly to metabolites with significantly less or absent antibacterial activity (Chapter 5). Pefloxacin is highly metabolized, principally to desmethyl (norfloxacin) and N-oxide derivatives [41], and this is its major pathway of elimination, whereas transformation of ofloxacin—and therefore levofloxacin— to similar metabolites accounts for only 6% of the dose [42]. Fleroxacin has an intermediate profile with primary renal clearance, but desmethyl (extended half-life) and N-oxide derivatives account for some 20% of the administered dose. Biotransformation of enoxacin, primarily to oxoenoxacin, accounts for some 50% of the dose. For other agents, biotransformation to drug-specific combinations of oxoquinolones (the major metabolites of ciprofloxacin and norfloxacin) and N-formyl, N-sulfonyl, N-acetyl, and desethylenyl products forms a significant but minority elimination pathway [43]. The primary metabolites of moxifloxacin are N-sulfate and acyl-glucuronide [37].

The half-lives of pefloxacin and norfloxacin are prolonged in severe liver disease, and even less highly metabolized agents, such as ciprofloxacin, may accumulate in hepatic failure [44].

Transintestinal elimination of norfloxacin and ciprofloxacin is a minor excretory pathway, which may be exploited in the management of some forms of infective diarrhoea, for example, enterotoxigenic E. coli (ETEC) enteritis.

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