TABLE 1

Rat and human liver microsomal stability of indomethacin and its amide derivatives 1 to 4

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Compound

MW/LogPa

Rat Plasma/Microsomes Fraction Unboundb

t1/2 (min)
Rat
Human
min
Indomethacin 357/4.18 0.030/0.91c >90 >90
Amide 1 460/5.50 0.0045/0.13 1.0 1.5
Amide 2 450/5.85 0.0040/0.05 8.5 25
Amide 3 451/5.05 0.0070/0.14 8.0 23
Amide 4
414/3.54
0.030/0.93
>90
>90
  • MW, molecular weight.

  • a LogP values were calculated using ACD software (Advanced Chemical Development, Inc.).

  • b Fraction unbound estimates in rat plasma and rat liver microsomes were obtained using in silico models developed at Pfizer as described previously with human liver microsomes (Gao et al., 2008). Literature free fraction of indomethacin in rat plasma is 0.040 (Dawidowicz et al., 2008), indicating high confidence in the in silico predictions.