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Vol. 29, Issue 8, 1136-1145, August 2001
Global Metabolism and Investigative Sciences (J.G.S., K.L.F.,
J.P.S., M.G.J., P.E.S., M.J.H., P.E.F., R.P.S., G.W.P., E.M.S.),
Clinical Pharmacology (D.J.S., I.R.W.), and Infectious Diseases
Clinical Research (J.B.B.), Pharmacia Corporation, Kalamazoo, Michigan
Linezolid (Zyvox), the first of a new class of antibiotics, the
oxazolidinones, is approved for treatment of Gram-positive bacterial
infections, including resistant strains. The disposition of linezolid
in human volunteers was determined, after a 500-mg (100-µCi) oral
dose of [14C]linezolid. Radioactive 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% (range 91.2-95.2%, n = 15), of which 83.9 ± 3.3% (range 76.7-88.4%) was in urine and 9.9 ± 3.4% (range 5.3-16.9%) was in feces. There was no major difference
in rate or route of excretion of radioactivity by dose regimen.
Linezolid was excreted primarily intact, and as two inactive,
morpholine ring-oxidized metabolites, PNU-142586 and PNU-142300. Other
minor metabolites were characterized by high-performance liquid
chromatography-atmospheric pressure chemical ionization-mass
spectrometry and 19F NMR spectroscopy. After the
single radioactive dose, linezolid was the major circulating
drug-related material accounting for about 78% (male) and 93%
(female) of the radioactivity area under the curve (AUC).
PNU-142586 (Tmax of 3-5 h) accounted for
about 26% (male) and 9% (female) of the radioactivity AUC. PNU-142300 (Tmax of 2-3 h) accounted for about 7%
(male) and 4% (female) of the radioactivity AUC. Overall, mean
linezolid and PNU-142586 exposures at steady-state were similar across
sex. In conclusion, linezolid circulates in plasma mainly as parent
drug. Linezolid and two major, inactive metabolites account for the
major portion of linezolid disposition, with urinary excretion
representing the major elimination route. Formation of PNU-142586
was the rate-limiting step in the clearance of linezolid.
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