Abstract
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.
Footnotes
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This study was presented in part at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1998, pp 17, San Diego, CA.
- Abbreviations used are::
- CV
- coefficient of variation
- LSC
- liquid scintillation counting
- ARE
- amount remaining to be excreted
- HPLC-APCI-MS
- high-performance liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry
- SPE
- solid-phase extraction
- AUC
- area under the curve
- CL/F
- total apparent oral clearance
- CLr/F
- renal clearance
- Received January 26, 2001.
- Accepted April 27, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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