WIENKERS LC, WYNALDA MA, FEENSTRA KL, GAO P, SLATTER JG; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 3 (abstract no. 11).

Pharmacia and Upjohn, Kalamazoo, MI.

The oxazolidinone antibiotic linezolid was evaluated for the potential to induce or inhibit cytochrome P450 enzymes. Cytochrome P450 Induction: Sprague-Dawley rats received 10, 40, and 125/80 mg/kg/day oral linezolid for 90 days (125 mg dose was reduced on day 40). Hepatic microsomal CYP1A, CYP3A and CYP4A were not induced. Levels of CYP2B were increased 1.5-fold in high dose males only, vs. 62-fold in a phenobarbital +ve control. Levels of CYP2E were increased 1.5-fold in high dose males only, vs. 5.6-fold in an isoniazid +ve control. Cytochrome P450 Inhibition: Linezolid at 10 and 100 uM did not inhibit cloned human cytochrome P450s, CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. Therefore, drug interactions mediated through inhibition of cytochrome P450 by linezolid are unlikely. Mechanism of Linezolid Oxidation: The unstable hemiacetal PNU-143011 mediates formation of the major human metabolite, PNU-142586. PNU-143011 formation was microsome- and NADPH-dependent and linear up to 700 uM. Rates of PNU-143011 formation in a human liver microsome panel did not correlate with component cytochrome P450s. Linezolid oxidation was not inhibited by P450 inhibitors, and was not mediated by flavin-dependent monooxygenases. PNU-143011 formation rate increased with pH over the pH range 4-9 and linezolid was oxidized by the Fenton reagent. Linezolid had a lower susceptibility to oxidation (0.9 V) than trolox or ascorbate. Linezolid oxidation was inhibited by antioxidants, and by deferoxamine. Collectively, these data indicate that linezolid undergoes a slow nonenzymatic oxidation, mediated by ubiquitous reactive oxygen species in vivo. In summary: Drug interactions related to induction or inhibition of cytochrome P450 enzymes by linezolid are not likely.

Publication Types:

• Meeting Abstracts

Keywords:

• Acetamides
• Animals
• Aryl Hydrocarbon Hydroxylases
• Cytochrome P-450 CYP1A2
• Cytochrome P-450 CYP3A
• Cytochrome P-450 Enzyme System
• Humans
• In Vitro
• Male
• Microsomes
• Mixed Function Oxygenases
• Oxazolidinones
• Oxidation-Reduction
• Oxidoreductases, N-Demethylating
• Phenylurea Compounds
• Rats
• S-mephenytoin N-demethylase
• enzymology
• linezolid
• metabolism
• pyriminil

Other ID:

• GWAIDS0007148

UI: 102244644

From Meeting Abstracts