TABLE 1

Identification of human, cynomolgus monkey, and rat AO substrates using a liver cytosol assay that incorporates monitoring loss of substrate and formation of hydroxylated metabolite

CompoundHumanCynomolgus MonkeyRat
t1/2a[O] MetaboliteaAO
Substratet1/2a[O] MetaboliteaAO Substratet1/2a[O] MetaboliteaAO Substrate
min% Estimatemin% Estimatemin% Estimate
UnknownsA-77-012 ± 0.0154 ± 0.4Y1 ± 0.0246 ± 3Y2 ± 0.154 ± 7Y
AMG 900281 ± 214 ± 1Y>5001 ± 0.2N>5002 ± 0.3N
AT-9283>5000N>5000N>5000N
Bafetinib2 ± 0.30Yb2 ± 0.40Yb11 ± 0.050Yb
Bosutinib>5000N>5000N>5000N
Cabozantinib>5000N>5000N>5000N
Ceritinib>5000N>5000N>5000N
CHIR99021>5002 ± 0.01N211 ± 631 ± 2Y>5002 ± 0.006N
CL-38778513 ± 329 ± 1Y4 ± 0.325 ± 0.7Y4 ± 10Yb
Dasatinib>5000N>5000N>5000N
Duvelisib449 ± 1912 ± 0.7Y>5000N>5001 ± 0.2N
Erlotinib>5000N>5000N>5000N
GDC-0068>5000N>50010 ± 0.6Y>5001 ± 0.03N
Gefitinib>5000N>5000N>5000N
Imatinib>5006 ± 0.3Y58 ± 161 ± 0.6Y>5005 ± 0.2Y
INCB 28060268 ± 617 ± 0.1Y44 ± 543 ± 1Y85 ± 0.541 ± 0.6Y
KIRA6>5000N>5000N>5000N
Lapatinib167 ± 237 ± 0.8Y241 ± 165 ± 1Y>5000N
Lapatinib_M119 ± 313 ± 1Y3 ± 0.225 ± 2Y423c21 ± 5Y
LDN-1931892 ± 0.0258 ± 0.5Y2 ± 0.0654 ± 6Y38 ± 1110 ± 28Y
LDN-211904>5000N>5000N>5000N
Linsitinib>5000N>5000N>5000N
ML-3476 ± 116 ± 0.2Y6 ± 0.43 ± 0.3Y25 ± 44 ± 0.5Y
Neratinib117 ± 10N>5000N142 ± 191 ± 0.1N
Oclacitinib>5000N>5000N>5000N
OSI-027>5000N>5000N>5000N
OXA-01>5000N>5000N>5000N
Ruxolitinib>5000N>5000N>5000N
SB-52533431 ± 155 ± 0.5Y9 ± 0.573 ± 0.7Y>5004 ± 0.1Y
SGI-1776>5000N>5000N>5000N
Sorafenib>5000N>5000N>5000N
THZ1256 ± 20N235 ± 70N231 ± 310N
Vatalanib>5000N>5000N>5000N
Venetoclax>5000N>5000N>5000N
Positive controlsCarbazeran2 ± 0.134 ± 0.1Y2 ± 0.0328 ± 0.8Y7 ± 0.524 ± 0.1Y
O6-Benzylguanine48 ± 343 ± 1Y52 ± 0.533 ± 0.4Y>5003 ± 0.05N
VX-509372 ± 3226 ± 0.5Y105 ± 1065 ± 6Y394 ± 5039 ± 2Y
XK469>5001 ± 0.003N121 ± 1219 ± 0.4Y428 ± 292 ± 0.1Y
Zoniporide44 ± 0.7127 ± 3Y24 ± 1129 ± 5Y9 ± 0.7185 ± 37Y
Negative controls4-Aminobiphenyl106 ± 350N
Dapsone>5000N
Clopidogrel21 ± 10N
Oseltamivir107 ± 10N
Enalapril340 ± 1220N
Fenofibrate8 ± 10N
  • a Data are mean (n = 2) ± S.E.

  • b Presence of AO metabolite(s) confirmed in site of oxidation study. Further metabolism of initial AO metabolite observed.

  • c Insufficient data for S.E. calculation.