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

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-mCi) oral dose of [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 5 4/sex/regimen). Mean recovery of radioactivity in excreta was 93.8 6 1.1% (range 91.2–95.2%, n 5 15), of which 83.9 6 3.3% (range 76.7–88.4%) was in urine and 9.9 6 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 ionizationmass spectrometry and 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 (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. Linezolid ((S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5oxazolidinyl]methyl]-acetamide, Zyvox, PNU-100766; Fig. 1) is the first of a new class of antibiotics, the oxazolidinones. Linezolid is approved in the United States and other countries worldwide for the treatment of Gram-positive bacterial infections, including those caused by resistant organisms. The oxazolidinones are synthetic compounds that selectively inhibit the initiation phase of bacterial protein synthesis (Swaney, 1996; Demyan et al., 1997; Lin et al., 1997; Shinabarger et al., 1997). Linezolid is dosed intravenously or orally at 400 or 600 mg b.i.d. Because bioavailability is approximately 100%, no dosage adjustment is needed when changing from intravenous to oral therapy. After an oral 600-mg dose, steady-state peak plasma concentrations of 21.2 6 5.78 mg/ml are obtained at a Tmax of 1.03 6 0.62 h. The plasma elimination half-life is 5.40 6 2.06 h. Clearance, which occurs by both renal and nonrenal (65%) mechanisms is 80 6 29 ml/min. Linezolid is neutral in the physiological pH range and undergoes renal tubular reabsorption. Plasma protein binding is low at 31%, and the volume of distribution approximates total body water (40–50 liters) (Pawsey et al., 1996, Stalker et al., 1997a,b; Pharmacia Corporation, 2000). In a single-dose study, female human subjects had about 20% lower body weight-normalized clearance than males (Sisson et al., 1999). The objective of this study was to determine the pharmacokinetics, metabolism, and excretion of linezolid following single-dose and steady-state administration of [C]linezolid to healthy human subjects. Materials and Methods Study Design. The study enrolled 16 healthy volunteers (four subjects per sex for each regimen) aged 20 to 61 years. All subjects provided written informed consent prior to enrollment. Radiation exposure estimates for human tissues were predicted using maximum internal radiation dose (MIRD) software (Loevinger et al., 1991). The 100-mCi dose chosen for this study is similar to that given in most other human C trials conducted in the United States (Dain et al., 1994). In a randomized, open-label, parallel group study, the single-dose group received a single 500-mg oral dose of [C]linezolid solution (100 mCi), administered on the morning of day 1. In the steady-state group, two 250-mg linezolid tablets were given every 12 h on days 1 to 3. On day 4 a single 500-mg oral dose of [C]linezolid solution (100 mCi) was given as the AM dose then two 250-mg linezolid tablets as the PM dose, followed on days 5 to 10 by two 250-mg linezolid tablets every 12 h. Adverse events were all nonserious and mild to moderate in intensity, with no clinically significant laboratory or ECG abnormalities. Formulations and Dose Administration. Linezolid 250-mg tablets were from lot 27,721 (single-dose) or lot 27,872 (steady-state dose). Linezolid was This study was presented in part at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1998, pp 17, San Diego, CA. Address correspondence to: Dr. J. Greg Slatter, Global Metabolism and Investigative Sciences, Pharmacia Corporation, 301 Henrietta St., Kalamazoo MI 49007. E-mail: [email protected] 0090-9556/01/2908-1136–1145$3.00 DRUG METABOLISM AND DISPOSITION Vol. 29, No. 8 Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics 346/920554 DMD 29:1136–1145, 2001 Printed in U.S.A. 1136 at A PE T Jornals on O cber 9, 2017 dm d.aspurnals.org D ow nladed from