TABLE 1

Pharmacokinetic parameters of methotrexate in wild-type and Abcc3-/-mice given by intravenous infusion and single oral administration Data were taken from intravenous infusion and single oral dose studies, and ex vivo plasma protein binding and blood to plasma partition assays. The details of pharmacokinetic analyses are described under Materials and Methods. CLtot,p, CLbile,p, CLr,p, and CLbile,liver were calculated from eqs. 1, 2, 3, and 4, respectively. AUCpo was calculated from eq. 8, and F, Fh, and FaFg were calculated from eqs. 5, 6, and 7, respectively. Each value represents the mean ± S.D. of at least four independent experiments.






Wild-Type

Abcc3–/–
R b 0.571 ± 0.034 0.611 ± 0.039
f p 0.661 ± 0.045 0.703 ± 0.051
νbile μmol/h/kg 0.128 ± 0.027 0.132 ± 0.012
νurine μmol/h/kg 0.0760 ± 0.0181 0.0566 ± 0.0078
C p,ss nmol/ml 0.150 ± 0.036 0.0942 ± 0.0249*
C liver nmol/g 1.40 ± 0.18 1.48 ± 0.07
C kidney nmol/g 1.36 ± 0.20 1.46 ± 0.08
CLtot,p ml/min/kg 25.5 ± 5.7 39.2 ± 3.3*
CLbile,p ml/min/kg 14.9 ± 5.3 23.4 ± 2.4*
CLr,p ml/min/kg 9.05 ± 3.84 10.4 ± 1.1
CLbile,liver ml/min/kg 1.65 ± 0.50 1.50 ± 0.23
Kp liver 9.43 ± 2.86 15.7 ± 1.2*
Kp kidney 9.21 ± 3.38 15.7 ± 2.6*
AUC po nmol × h/ml 0.541 ± 0.131 0.159 ± 0.044*
F 0.360 0.160
F h 0.729 0.557
F a F g

0.493
0.287
  • * P < 0.05, significantly different from wild-type mice