High performance liquid chromatographic analysis and pharmacokinetic investigation of oxacillin and its metabolites in man.

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Pharmacokinetic evaluation of oxacillin in man was carried out by detailed investigation of the urinary excretion profiles of unchanged oxacillin and metabolites. A new metabolite, penicilloic acid of the 5-hydroxymethyl derivative of oxacillin, was discovered in human urine excreted after oral administration of oxacillin. This metabolite was formed by cleavage of the β-lactam ring of the 5-hydroxymethyl derivative (a known active metabolite of oxacillin), not by hydroxylation of the 5-methyl group on the isoxazolyl moiety of penicilloic acid of oxacillin. The time courses of excretion of the new metabolite as well as unchanged oxacillin and known metabolites (penicilloic acid and 5-hydroxymethyl derivative) were measured by HPLC analysis of urine excreted after oral administration of oxacillin tablets to human subjects. The values for cumulative excretion amount at infinite time (X∞) and mean residence time (MRT) for each species were estimated by moment analysis of excretion rate vs. time curves. The rate constants for absorption, metabolism, and urinary excretion were calculated by non-linear least-squares fittings of the time course data using a one compartment model. The results indicate that the excretion ratio (X∞/D, D=500 mg) and MRT value as averages of five subjects are 27.4% and 1.76 h for unchanged oxacillin, 16.1% and 3.79 h for penicilloic acid, 22.2% and 2.04 h for 5-hydroxymethyl derivative, and 22.4% and 3.89 h for penicilloic acid of the 5-hydroxymethyl derivative. The conversion ratio at each elimination step and the MRT value intrinsic to each metabolite were evaluated from the results of moments.

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