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Vol. 28, Issue 9, 1014-1017, September 2000
Drug Metabolism Research In vitro studies were conducted to identify the hepatic enzyme(s)
responsible for the oxidative metabolism of linezolid. In human liver
microsomes, linezolid was oxidized to a single metabolite, hydroxylinezolid (M1). Formation of M1 was determined to be dependent upon microsomal protein and NADPH. Over a concentration range of 2 to
700 µM, the rate of M1 formation conformed to first-order (nonsaturable) kinetics. Application of conventional in vitro techniques were unable to identify the molecular origin of M1 based on
the following experiments: a) inhibitor/substrates for various
cytochrome P-450 (CYP) enzymes were unable to inhibit M1 formation; b)
formation of M1 did not correlate (r2 < 0.23) with any of the measured catalytic activities across a
population of human livers (n = 14); c) M1
formation was not detectable in incubations using microsomes prepared
from a baculovirus insect cell line expressing CYPs 1A1, 1A2, 2A6, 2B6,
2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 4A11. In addition, results
obtained from an in vitro P-450 inhibition screen revealed that
linezolid was devoid of any inhibitory activity toward the following
CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Additional in vitro studies excluded the possibility of
flavin-containing monooxygenase and monoamine oxidase as potential
enzymes responsible for metabolite formation. However, metabolite
formation was found to be optimal under basic (pH 9.0) conditions,
which suggests the potential involvement of either an uncharacterized
P-450 enzyme or an alternative microsomal mediated oxidative pathway.
Pharmacia Corporation
Kalamazoo,
Michigan
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