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Department of Drug Metabolism and Pharmacokinetics,
Rhone-Poulenc Rorer
The specificities of orphenadrine and methimazole on eight human
liver P450 enzyme activities were evaluated by studying the extent of
inhibition at different concentrations in two protocols: competitive
inhibition and preincubation. In the competitive inhibition protocol,
orphenadrine decreased CYP2B6 marker activity up to 45-57% in human
liver microsomes and up to 80-97% in cell microsomes containing
cDNA-expressed CYP2B6. Orphenadrine strongly decreased CYP2D6 marker
activity by 80-90%. Orphenadrine also partially decreased the CYP1A2,
CYP2A6, CYP3A4, and CYP2C19 marker activities. In the preincubation
protocol, orphenadrine decreased the CYP2B6 activity in cDNA-expressed
cell microsomes to completion. In human liver microsomes, orphenadrine
strongly decreased the marker activities of CYP2B6, CYP2D6, as well as
CYP2C9; and partially decreased the marker activities of CYP1A2,
CYP2A6, CYP3A4, and CYP2C19. In the competitive inhibition protocol,
methimazole had no effect on the marker activities of CYP2E1 and
CYP2A6; slightly decreased CYP2D6 marker activity; partially decreased
the marker activities of CYP2C19, CYP2C9, and CYP2B6; and dramatically
decreased CYP3A4 marker activity. Methimazole decreased CYP1A2 marker
activity at lower concentrations, but not at the highest concentration studied (1 mM). In the preincubation protocol, methimazole was shown to
be a potent and nonspecific inhibitor of all the enzyme activities.
Marker activities of CYP2C9, CYP2C19, and CYP3A4 were completely
inhibited at relatively low concentrations. This study indicates
orphenadrine cannot be used as a selective inhibitor of CYP2B6 in human
liver microsomes and that methimazole is not a selective inhibitor of
the flavin-containing monooxygenase in human liver microsomes.
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