Slatter J G, Stalker D J, Feenstra K L, Welshman I R, Bruss J B, Sams J P, Johnson M G, Sanders P E, Hauer M J, Fagerness P E, Stryd R P, Peng G W, Shobe E M
Global Metabolism and Investigative Sciences, Pharmacia Corporation, 301 Henrietta St., Kalamazoo, MI 49007, USA.
Drug Metab Dispos. 2001 Aug;29(8):1136-45.
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-microCi) 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.
利奈唑胺（Zyvox）是新型抗生素恶唑烷酮类中的首个药物，被批准用于治疗革兰氏阳性菌感染，包括耐药菌株。在口服500毫克（100微居里）的[(14)C]利奈唑胺后，测定了利奈唑胺在人体志愿者体内的处置情况。放射性利奈唑胺以单剂量给药，或在未标记利奈唑胺的10天、500毫克每日两次给药方案的第4天达到稳态时给药（每种给药方案男女各4例）。排泄物中放射性的平均回收率为93.8±1.1%（范围91.2 - 95.2%，n = 15），其中83.9±3.3%（范围76.7 - 88.4%）通过尿液排出，9.9±3.4%（范围5.3 - 16.9%）通过粪便排出。不同给药方案的放射性排泄速率和途径没有显著差异。利奈唑胺主要以原形排泄，并产生两种无活性的吗啉环氧化代谢产物PNU - 142586和PNU - 142300。其他次要代谢产物通过高效液相色谱 - 大气压化学电离 - 质谱法和(19)F核磁共振光谱法进行鉴定。单次放射性剂量给药后，利奈唑胺是主要的循环药物相关物质，占曲线下放射性面积（AUC）的约78%（男性）和93%（女性）。PNU - 142586（T(max)为3 - 5小时）占放射性AUC的约26%（男性）和9%（女性）。PNU - 142300（T(max)为2 - 3小时）占放射性AUC的约7%（男性）和4%（女性）。总体而言，稳态时利奈唑胺和PNU - 142586的平均暴露量在性别间相似。总之，利奈唑胺在血浆中主要以母体药物形式循环。利奈唑胺及其两种主要的无活性代谢产物占利奈唑胺处置的主要部分，尿液排泄是主要的消除途径。PNU - 142586的形成是利奈唑胺清除的限速步骤。
