TABLE 1

Metabolite profiling data for lapatinib (50 μM) incubated with NADPH-fortified human liver microsomes (1 mg/ml), recombinant CYP3A4, or recombinant CYP3A5 (100 pmol/ml) for 30 minutes and re-isolated by ultracentrifugation (100,000g; 60 minutes)

IdentityRetention Time Relative to LapatinibExperimental m/zaMass Shift from LapatinibProposed Elemental CompositionTheoretical m/zMass ErrorProposed Biotransformation
ppm
M10.50473.1052−108.0373C22H21ClN4O4S473.10500.4O-Dealkylation
M20.78489.0995−92.0430C22H21ClN4O5S489.0999−0.8O-Dealkylation + oxygenation
M30.95597.1367+15.9941C29H26ClFN4O5S597.1375−1.3Oxygenation
M40.97475.1336−106.0090C26H20ClFN4O2475.1337−0.2N-Dealkylation
Lapatinib1.00581.1427+0.0002C29H26ClFN4O4S581.14260.2N.A. (Parent)
M51.10613.1331+31.9906C29H26ClFN4O6S613.13241.1Dioxygenation
M61.11595.1220+13.9795C29H24ClFN4O5S595.12180.3N-Oxygenation + further oxidation to the nitrone
M71.13476.1176−105.0249C26H19ClFN3O3476.1177−0.2N-Dealkylation to yield aldehyde + reduction to the alcohol
M81.14597.1368+15.9943C29H26ClFN4O5S597.1375−1.2N-Oxygenation
M91.18489.1125−92.0300C26H18ClFN4O3489.1130−1.0N-Dealkylation + N-hydroxylation with further oxidation to yield the nitroso/oxime
M101.21474.1016−107.0409C26H17ClFN3O3474.1021−1.1N-Dealkylation to yield aldehyde
  • a Accurate m/z values taken from the low energy MSE data set.