Pharmacokinetics, metabolism, and excretion of linezolid following an oraldose of [C-14]linezolid to healthy human subjects

Linezolid (Zyvox), the first of a new class of antibiotics, the oxazolidino nes, is approved for treatment of Gram-positive bacterial infections, inclu ding resistant strains. The disposition of linezolid in human volunteers wa s determined, after a 500-mg (100-mu Ci) oral dose of [C-14]linezolid. Radi oactive linezolid was administered as a single dose, or at steady-state on day 4 of a 10-day, 500-mg b.i.d. regimen of unlabeled linezolid (n = 4/sex/ regimen). Mean recovery of radioactivity in excreta was 93.8 +/- 1.1% (rang e 91.2-95.2%, n = 15), of which 83.9 +/- 3.3% (range 76.7-88.4%) was in uri ne and 9.9 +/- 3.4% (range 5.3-16.9%) was in feces. There was no major diff erence in rate or route of excretion of radioactivity by dose regimen. Line zolid was excreted primarily intact, and as two inactive, morpholine ring-o xidized metabolites, PNU-142586 and PNU-142300. Other minor metabolites wer e characterized by high-performance liquid chromatography-atmospheric press ure chemical ionization-mass spectrometry and F-19 NMR spectroscopy. After the single radioactive dose, linezolid was the major circulating drug-relat ed material accounting for about 78% (male) and 93% (female) of the radioac tivity area under the curve (AUC). PNU-142586 (T-max of 3-5 h) accounted fo r about 26% (male) and 9% (female) of the radio-activity AUC. PNU-142300 (T -max of 2-3 h) accounted for about 7% (male) and 4% (female) of the radioac tivity AUC. Overall, mean linezolid and PNU-142586 exposures at steady-stat e were similar across sex. In conclusion, linezolid circulates in plasma ma inly as parent drug. Linezolid and two major, inactive metabolites account for the major portion of linezolid disposition, with urinary excretion repr esenting the major elimination route. Formation of PNU-142586 was the rate- limiting step in the clearance of linezolid.