Human metabolism of cefotaxime

Following the administration of a single dose of cefotaxime (CTAX) to patients with renal failure, we observed two previously undescribed peaks termed ‘unknown peaks 1 and 2’ (= UP1 and UP2) in serum analysed by high-pressure liquid chromatography. Together with the desacetyl metabolite of CTAX (DACM), UP1 and UP2 reached their maximum concentrations (5 to 10 mg/1 measured as DACM) at about 6 h after administration and persisted with a very long half-life (greater than 12 h). The half-life of CTAX was 1.5 to 3.5 h. No CTAX-lactone could be detected. Subsequent investigations in a normal volunteer receiving 1 g CTAX intramuscularly showed the presence of very low concentrations of UP1 and UP2 in the plasma but significant concentrations in the urine, each amounting to 6% of the dose given. The overall recovery was 90%. The chemical structures of UP1 and UP2 are at present undetermined. UP1 and UP2 are microbiologically inactive. They are formed in vitro by degradation of CTAX-lactone by β-lactamase or alkali, but are themselves stable to further degradation by β-lactamase and are not formed from CTAX or DACM, suggesting that UP1 and UP2 may be stable lactone forms with an open β-lactam ring. The pharmacokinetic characteristics of UP1, UP2 and DACM suggest that they will accumulate during multi-dosing of CTAX in renal failure. As metabolites form an important part of the disposition of CTAX, pharmacokinetic studies without their estimation may be considered as incomplete.