Pharmacokinetics, Metabolism, and Excretion of Linezolid following an Oral Dose of [14C]Linezolid to Healthy Human Subjects

• Published in: Drug metabolism and disposition Vol. 29; no. 8; pp. 1136 - 1145
• Main Authors: SLATTER, J. G, STALKER, D. J, STRYD, R. P, PENG, G. W, SHOBE, E. M, FEENSTRA, K. L, WELSHMAN, I. R, BRUSS, J. B, SAMS, J. P, JOHNSON, M. G, SANDERS, P. E, HAUER, M. J, FAGERNESS, P. E
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-08-2001
• Subjects: Acetamides - blood; Acetamides - pharmacokinetics; Acetamides - urine; Adult; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - urine; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Biotransformation; Chromatography, High Pressure Liquid; Feces - chemistry; Female; Fluorine Radioisotopes; Half-Life; Humans; Isotope Labeling; Linezolid; Male; Mass Spectrometry; Medical sciences; Middle Aged; Oxazolidinones - blood; Oxazolidinones - pharmacokinetics; Oxazolidinones - urine; Pharmacology. Drug treatments; Spectrophotometry, Ultraviolet; Whole-Body Counting; Multiple dose; Human; Linezolid; Antibiotic; Healthy subject; Single dose; Elimination; Oral administration; Antibacterial agent; Metabolism; Pharmacokinetics
• ISSN: 0090-9556; 1521-009X

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 [ 14 C]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 19 F 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 ( T max of 3–5 h) accounted for about 26% (male) and 9% (female) of the radioactivity AUC. PNU-142300 ( T max 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.