Abstract

The oxazolidinone antibacterial linezolid has been in clinical use for over twenty years, yet knowledge of the contributions of specific cytochrome P450 enzymes to the metabolic clearance of this drug were mostly unknown. In this investigation it was revealed that three P450 enzymes that had not been previously explored in linezolid metabolism, CYP2J2, CYP4F1, and CYP1B1, catalyzed the 2-hydroxylation and deethyleneation of the morpholine moiety of linezolid. The intrinsic clearance for linezolid metabolism in pooled human liver microsomes was low at 0.51 µL/min/mg protein, consistent with its in vivo clearance in humans, and the K_M was high (>200 µM). In recombinant human P450 enzymes, a rank order of intrinsic clearance values for linezolid 2-hydroxylation were CYP2J2>>CYP4F2>CYP2C8>CYP1B1≈CYP2D6≈CYP3A4>CYP1A1>CYP3A5, with nine other P450 enzymes showing no linezolid metabolism The effect of selective inhibitors for these eight P450 enzymes on linezolid metabolism in pooled human liver microsomes was evaluated to provide estimates of the relative fractional contributions of these enzymes to linezolid metabolism. These experiments suggest that CYP2J2 and CYP4F2 contribute about 50% each to linezolid hepatic metabolism. It is proposed that the oxidative metabolic clearance of linezolid is primarily catalyzed by these two unusual P450 enzymes and that this explains the lack of observation of meaningful effects of common perpetrators of drug interactions on linezolid pharmacokinetics.

Significance Statement Linezolid is an important antibacterial drug, but the enzymes involved in its oxidative metabolism were unknown. In this paper, evidence is shown that supports an important role for two enzymes not frequently associated with the metabolism of drugs: CYP2J2 and CYP4F2. These observations offer insight to understand the results of clinical drug-drug interaction studies conducted on linezolid.