Pharmacokinetics and Tissue Penetration of Linezolid following Multiple Oral Doses

Abstract

The pharmacokinetics of multiple-dose linezolid were determined following administration of five 600-mg oral doses given every 12 h to each of six healthy male volunteers. Concentrations of the drug were determined in plasma and inflammatory blister fluid using high-pressure liquid chromatography. A mean peak concentration in plasma of 18.3 g/ml (standard deviation [SD], 6.0) was attained at a mean time of 0.7 h (SD, 0.3) after the final dose. The penetration into the inflammatory fluid was 104% (SD, 20.7). A mean peak concentration of 16.4 g/ml (SD, 10.6) was attained in the inflammatory fluid at 3 h (SD, 0.6) after the final dose. The elimination half-life from serum and inflammatory fluid was 4.9 (SD, 1.8) and 5.7 (SD, 1.7) h, respectively. The area under the concentration-time curve in plasma and blister fluid was 140.3 (SD, 73.1) and 155.3 (SD, 80.1) g ⅐ h/ml, respectively. These data suggest that linezolid has good tissue penetration, and we can predict that it will be successful in the treatment of a variety of gram-positive infections.Linezolid belongs to a new class of antibiotics, the oxazolidinones. It acts by selectively inhibiting the initiation of bacterial protein synthesis and has been shown to possess in vitro and in vivo activity against gram-positive organisms, including Streptococcus pneumoniae strains that are resistant to penicillin, methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium with phenotypes Van A, B, and C (2,6,9,11,13). The aim of this study was to assess the pharmacokinetics and tissue penetration of linezolid following multiple oral doses of 600 mg. A blister technique was used to assess tissue penetration since blister fluid mimics inflammatory exudate and hence is a model of likely pharmacokinetics at the site of infection (10). MATERIALS AND METHODSSubjects. Eight healthy volunteers, with a mean age of 29.6 years (standard deviation [SD], 8.7), a mean weight of 78.6 kg (SD, 7.1), and a mean height of 180.4 cm (SD, 14.1), gave written informed consent to participate in this study. One volunteer was unable to attend the actual study day due to febrile illness; therefore, only seven participants were studied. Exclusion criteria for the trial included any history of significant illness or atopy, recent participation in another drug trial, and use of prescription or nonprescription drugs (particularly monoamine oxidase inhibitors) within 14 or 7 days of the study, respectively. All volunteers underwent a full medical history, an examination and a full blood count, clotting, renal, and liver function tests, and urinalysis and a urine drugsof-abuse screen, all of which were normal. The hospital's ethics committee granted approval for this study.Drug administration. The volunteers were given one 600-mg linezolid tablet every 12 h for 2.5 days (a total of five doses). The first dose was given in the hospital with the physician present for the first hour. Doses two and three were self-administered by the volunteer at home. This was confirmed b...

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