This metabolic pathway leads to two major inactive metabolites (which each account for around 45% and 10% of an excreted dose at steady state), one minor metabolite, and several trace metabolites, none of which accounts for more than 1% of an excreted dose. Clearance of linezolid varies with age and gender; it is fastest in children (which accounts for the shorter half-life), and appears to be 20% lower in women than in men. There is a strong correlation between linezolid clearance and creatinine clearance. Chemistry
At physiological pH (7.4), linezolid exists in an uncharged state. It is moderately water-soluble (approximately 3 mg/mL), with a logP of 0.55. The oxazolidinone pharmacophore—the chemical "template" essential for antimicrobial activity—consists of a 1,3-oxazolidin-2-one moiety with an aryl group at position 3 and an S-methyl group, with another substituent attached to it, at position 5 (the R-enantiomers of all oxazolidinones are devoid of antibiotic properties). In addition to this essential core, linezolid also contains several structural characteristics that improve its effectiveness and safety. An acetamide substituent on the 5-methyl group is the best choice in terms of antibacterial efficacy, and is used in all of the more active oxazolidinones developed thus far; in fact, straying too far from an acetamide group at this position makes the drug lose its antimicrobial power, although weak to moderate activity is maintained when some isosteric groups are used.
Studies of the compounds structure–activity relationships led to the development of several subclasses of oxazolidinone derivatives, with varying safety profiles and antimicrobial activity. Two compounds were considered drug candidates: eperezolid (codenamed PNU-100592) and linezolid (PNU-100766). In the preclinical stages of development, they were similar in safety and antibacterial activity, so they were taken to Phase I clinical trials to identify any difference in pharmacokinetics. Linezolid was found to have a pharmacokinetic advantage—requiring only twice-daily dosage, while eperezolid needed to be given three times a day to achieve similar exposure—and therefore proceeded to further trials. The U.S. Food and Drug Administration (FDA) approved linezolid on 18 April 2000. Approval followed in Brazil (June 2000), the United Kingdom (January 2001), Japan and Canada (April 2001), Europe (throughout 2001), and other countries in Latin America and Asia.As of 2009, linezolid was the only oxazolidinone antibiotic available. Other members of this class have entered development, such as posizolid (AZD2563), ranbezolid (RBx 7644), and radezolid (RX-1741). In 2014, the FDA approved tedizolid phosphate, a second-generation oxazolidinone derivative, for acute bacterial skin and skin structure infection. Society and culture
Economics
Linezolid was quite expensive in 2009; a course of treatment may cost one or two thousand U.S. dollars for the drug alone, not to mention other costs (such as those associated with hospital stay). With the medication becoming generic the price has decreased.