Nalidixic acid pharmacokinetics

Since the introduction of nalidixic acid in 1963, structural modifications on the quinolones have been performed to improve either the antibacterial efficacy or pharmacokinetic/toxicologic profiles of these compounds. The newest quinolones possess broad-spectrum activity, favorable pharmacokinetic/toxicologic profiles, and potency against bacterial strains that are resistant to older generations of quinolones. This section describes the synthetic procedures for the new generation of quinolones that were studied during the 1995-2005 period. 

The pharmacokinetics of nalidixic and hydroxy-nalidixic acids have been studied by several different groups. Takasugi ejt al studied in-situ and in-vitro absorption of nalidixic acid from the gastrointestinal tracts of rats as a function of pH. They reported that the absorption of non-ionized nalidixic acid was faster than the ionized form, with the maximum absorption rate constant found when the drug was administered from a pH=3 buffer solution. The absorption in-sltu was found to be ten times the rate in-vitro, but this was dependent on several factors.(13)... 

The quinoline antibiotics are relatively late arrivals on the antibiotic scene. The parent compound of this class of drugs is nalidixic acid. The downside of this molecule is the rapid development of resistance by pathogenic bacteria. A major step forward was the introduction of a single fluorine atom at a key position, to yield new molecules such as ciprofloxacin, ofloxacin, levofloxacin, andmoxifloxacin. Of these, levofloxacin and moxifloxacin have the best combinations of spectrum of action, potency, and pharmacokinetic properties. In time, they are likely to largely replace the current quinoline antibiotic of choice, ciprofloxacin. Since these molecules work by a different mechanism than do the p-lactams, organisms that become resistant to the latter are generally susceptible to the former. 

The pharmacokinetics and tissue levels of nalidixic acid were determined after oral administration of a single dose of 40 mg drug/kg bw to cultured rainbow trout and amago salmon held at 15 C (181). The absorption rate of the drug was found to be nearly equal for the two species and was completed within 48 h. Nalidixic acid could be detected in all tissues of both species at as early as 0.5 h after dosing. 

K Uno, T Aoki, R Ueno, I Maeda. Pharmacokinetics of nalidixic acid and sodium nifurstyrenate in cultured fish following bolus intravascular administration. Fish Pathol 31 191-196, 1996. 

Introduction of the first fluorinated quinolone, norfloxacin [nor FLOX a sin], has been rapidly followed by new members of this class. These agents are totally synthetic and are closely related structurally to an earlier quinolone, nalidixic acid [nal i DIX ik]. The principal member of this group is ciprofloxacin [sip ro FLOX a sin], which has the widest clinical application. Other antibiotics in this group available in the United States are primarily employed to treat urinary infections (Figure 32.1). It seems likely that the size of this class of antibiotics will increase due to its wide antibacterial spectrum, favorable pharmacokinetic properties and relative lack of adverse reactions. Unfortunately, their overuse has already led to the emergence of resistant strains resulting in limitations to their clinical usefulness. 

Portmann GA, McChesney EW, Stander H, Moore WE. Pharmacokinetic model for nalidixic acid in man. II. 

Portmann GA, McChesney EW, Stander H, Moore WE. Pharmacokinetic model for nalidixic acid in man. II. Parameters for absorption, metabolism, and elimination. Journal of pharmaceutical sciences. 1966 Jan 55(l) 72-8. 

It is recommended for the treaimenl of urinary tract infections caused by strains of Gram-negative bacteria susceptible to these agents. Early clinical studies indicate that the drug pos.sesses pharmacokinetic properties superior to those of either of its predece.ssors. Thus, following oral administration, higher urinary concentrations of cinoxacin than of nalidixic acid or oxolinic acid are achieved. Cinoxacin appears to be more completely absorbed and less protein bound than nalidixic acid. 

Most studies show that the quinolones have, at most, a small, clinically insigniilcant effect on the pharmacokinetics and pharmacodynamics of warfarin. Despite this, increased effects and even bleeding have been seen quite unpredictably in isolated cases in patients taking warfarin with ciprofloxacin, gatifloxacin, levo-floxacin, moxifloxacin, nalidixic acid, norfloxacin or ofloxacin or while taking acenocoumarol when given nalidixic acid, norfloxacin or pefloxacin, or phenprocoumon with norfloxacin. Fur-... 

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