Absorption, excretion, and metabolism of a new antibacterial agent, nalidixic acid

Studies of the absorption, excretion, and metabolism of a new antibacterial agent, nalidixic acid, have been made. The compound is rapidly absorbed when given in capsule or tablet form, as the free acid; it is excreted in the urine by man, partly in the free (extractable, biologically available) form, but a much larger fraction as a monoglucuronide, and a considerable fraction is converted to the 7-hydroxymethyl metabolite. A lesser amount of the latter is also excreted in a conjugated form, and a rather minor excretion product is the 3,7-dicarboxylic acid. The conversion of nalidixic acid to conjugated and hydroxylated forms appears to begin almost immediately upon absorption. Of single or repeated oral doses, about 80% of nalidixic acid is recoverable from the urine as definitely characterized products; fecal excretion is of minor importance, although the drug does appear in the bile of monkey and dog. Supplementation of nalidixic acid medication with bicarbonate greatly increases the amount of naphthyridine excreted in the urine in a biologically available form (i.e., the unconjugated forms of nalidixic acid and its hydroxymethyl metabolite). The excretion of the hydroxymethyl metabolite when administered as such follows much the same general pattern as that of the parent compound. However, the former compound has less tendency to conjugation and bicarbonate supplementation further decreases the extent of conjugation to the point where nearly half of the orally ingested metabolite may appear in the urine in a biologically available form. When studied in dogs and monkeys following long-term administration at high dose levels, nalidixic acid is found to have little tendency to accumulate in any tissue; practically all tissues have lower concentrations than those existing concomitantly in the plasma. The highest tissue concentrations relative to plasma, in both species, are in kidney, and the lowest are in brain and fat.