TABLE 2

PK of dFdC, dFdU, and their nucleotides in plasma, liver, kidney, and PBMCs after 1qd×1d, 1qd×7d, and 7qd×1d i.v. dosing of dFdC 0.1 mg/kg Data are presented as mean ± S.D. (n ≥ 3).

dFdC
dFdU
dFdC-MP
dFdC-TP
dFdU-TP
Intravenous 1qd×1d
   Plasma
      AUC0–8 (h · pmol/ml) 327 ± 36 2129 ± 48 64 ± 4 9 ± 1 7 ± 1
      AUC0–24 (h · pmol/ml) 350 ± 39 3185 ± 85 102 ± 9 13 ± 1 11 ± 1
   t1/2 (h) 1.8 ± 0.3 4.4 ± 0.6 3.9 ± 0.6 4.5 ± 1.3 4.0 ± 0.7
   Cl (l/kg/h) 1.0 ± 0.1 n.a. n.a. n.a. n.a.
   Vd (l/kg) 12 ± 1.6 n.a. n.a. n.a. n.a.
   Liver
      AUC0–8 (h · pmol/g) 106 ± 35 1878 ± 227 168 ± 36 15 ± 1 24 ± 2
      AUC0–24 (h · pmol/g) 110 ± 35a** 2716 ± 155a** 210 ± 41a** 22 ± 1a** 37 ± 1a**
   Kidney
      AUC0–8 (h · pmol/g) 15 ± 1.0 3520 ± 219 297 ± 28 122 ± 4 78 ± 9
      AUC0–24 (h · pmol/g) 21 ± 1.5a** 4976 ± 668a** 530 ± 53a** 225 ± 18a** 147 ± 19a**
Intravenous 1qd×7d
   Plasma dFdC dFdU dFdC-MP dFdC-TP dFdU-TP
      AUC0–8 (h · pmol/ml) 348 ± 14 2495 ± 75 58 ± 4 9 ± 1 9 ± 1
      AUC0–24 (h · pmol/ml) 377 ± 40 4673 ± 131 114 ± 9 16 ± 1 16 ± 1
   t1/2 (h) 2.0 ± 0.3 5.9 ± 0.5 6.1 ± 1.0 8.1 ± 1.0 6.9 ± 0.8
   Liver
      AUC0–8 (h · pmol/g) 124 ± 32 2185 ± 32 199 ± 16 16 ± 2 29 ± 3
      AUC0–24 (h · pmol/g) 131 ± 32 3578 ± 158b** 284 ± 20b** 30 ± 5b** 55 ± 2b**
   Kidney
      AUC0–8 (h · pmol/g) 15 ± 2.0 3555 ± 289 336 ± 33 150 ± 16 115 ± 13
      AUC0–24 (h · pmol/g) 27 ± 4.0 5570 ± 377 657 ± 80 284 ± 37b** 208 ± 21b**
Intravenous 7qd×1d
   Plasma
      AUC0–8 (h · pmol/ml) 182 ± 148 9284 ± 1018 271 ± 34 37 ± 7 34 ± 6
   Liver
      AUC0–8 (h · pmol/g) 89 ± 53 6985 ± 143c***,d*** 353 ± 279c***,d*** 61 ± 11c***,d*** 101 ± 15c***,d***
   PBMCs
      AUC0–8 (h · pmol/g)
125 ± 42
2242 ± 380a**
5.6 ± 2.9a**
15 ± 2a**
16 ± 2a**

  • n.a., not available

  • ↵a** P < 0.01 for the comparison of the drug AUC between tissue (liver, kidney, and lung) or PBMCs and plasma

  • ↵b** P < 0.01 for the comparison of the drug AUC within tissues (liver and kidney) between 1qd×7d and 1qd×1d dosing

  • ↵c*** P < 0.001 for the comparison of the drug AUC within the liver between 7qd×1d and 1qd×7d dosing

  • ↵d*** P < 0.001 for the comparison of the drug AUC between the liver and PBMCs after 7qd×1d dosing