TABLE 1

Diclofenac and three primary metabolites as determined in bile, liver, and plasma of mice with cannulated gallbladder 60 min after intravenous administration of diclofenac at 5 mg/kg

Plasma concentrations are expressed as milligrams per liter, and liver and bile concentrations are given as percentage of the dose. Data are given as means ± S.D., n = 4 to 6.

Biological Matrix and CompoundGenotype
WTMrp2(−/−)Bcrp1(−/−)Mrp2/Bcrp1(−/−)
Bile (% of dose)
    Diclofenac0.036 ± 0.0330.033 ± 0.0070.042 ± 0.0140.044 ± 0.010
    Diclofenac AG4.22 ± 1.392.12 ± 0.33*1.96 ± 0.72*1.11 ± 0.22**†‡
    4′-Hydroxy diclofenac0.140 ± 0.0550.008 ± 0.004**0.145 ± 0.0340.007 ± 0.002***‡‡
    5-Hydroxy diclofenac0.053 ± 0.0240.022 ± 0.008*0.039 ± 0.0100.017 ± 0.003**‡
Liver (% of dose)
    Diclofenac4.57 ± 2.002.88 ± 1.233.92 ± 2.094.32 ± 1.44
    Diclofenac AG0.47 ± 0.230.36 ± 0.310.84 ± 0.28*†1.76 ± 0.40***††‡
    4′-Hydroxy diclofenac0.46 ± 0.170.42 ± 0.180.44 ± 0.200.42 ± 0.15
    5-Hydroxy diclofenac1.31 ± 0.590.77 ± 0.381.28 ± 0.450.94 ± 0.28
Plasma (mg/l)
    Diclofenac6.74 ± 3.063.75 ± 1.715.06 ± 3.396.54 ± 1.74
    Diclofenac AG0.23 ± 0.100.95 ± 0.16***0.30 ± 0.111.64 ± 0.49***†‡‡
    4′-Hydroxy diclofenac0.23 ± 0.110.19 ± 0.080.22 ± 0.160.21 ± 0.07
    5-Hydroxy diclofenac0.90 ± 0.300.58 ± 0.150.82 ± 0.320.63 ± 0.15
  • * P < 0.05 compared with WT mice.

  • ** P < 0.01 compared with WT mice.

  • *** P < 0.001 compared with WT mice.

  • P < 0.05 compared with Mrp2(−/−) mice.

  • †† P < 0.01 compared with Mrp2(−/−) mice.

  • P < 0.05 compared with Bcrp1(−/−) mice.

  • ‡‡ P < 0.01 compared with Bcrp1(−/−) mice.