Table 1.

AUC and tissue-to-plasma AUC ratios of topotecan

PlasmaBrainLiverKidneySpleenLungsHeart
Single agent
    WT475 ± 49150 ± 19 (0.32)4,807 ± 610 (10.1)16,197 ± 4,495 (34.1)4,672 ± 214 (9.8)1,951 ± 400 (4.1)1,190 ± 107 (2.5)
    Mdr1a/b(−/−)352 ± 17226 ± 21 (0.64, P < 0.01*)3,884 ± 377 (11.0)10,985 ± 4,445 (31.2)3,427 ± 159 (9.7)1,277 ± 72 (3.6)933 ± 66 (2.7)
    Bcrp1(−/−)1,118 ± 109239 ± 20 (0.21, NS*)10,143 ± 513 (9.1)10,367 ± 467 (9.3)6,109 ± 365 (5.5)4,456 ± 443 (4.0)2,893 ± 209 (2.6)
    Mdr1a/b(−/−)Bcrp1(−/−)1,759 ± 1181,794 ± 58 (1.02, P < 0.01*)14,573 ± 781 (8.4)19,506 ± 3,802 (11.1)16,263 ± 1,240 (9.3)6,936 ± 597 (3.9)4,270 ± 281 (2.4)
With elacridar
    WT1,332 ± 93680 ± 45 (0.51, P < 0.05)16,111 ± 1,328 (12.1)17,500 ± 1,348 (13.1)18,844 ± 1,025 (14.2)5,698 ± 328 (4.3)3,789 ± 257 (2.8)
    Mdr1a/b(−/−)1,395 ± 40651 ± 33 (0.47 P < 0.05)16,233 ± 699 (11.6)17,234 ± 855 (12.4)15,025 ± 668 (10.8)5,101 ± 174 (3.7)3,323 ± 91 (2.4)
    Bcrp1(−/−)2,226 ± 1792,209 ± 85 (0.99, P < 0.01)22,106 ± 1,823 (9.9)21,768 ± 1,687 (9.7)20,885 ± 750 (9.4)8,807 ± 637 (4.0)4,987 ± 408 (2.2)
    Mdr1a/b(−/−)Bcrp1(−/−)2,264 ± 1332,526 ± 137 (1.12, NS)22,152 ± 420 (9.8)23,687 ± 1,601 (10.5)27,240 ± 2,164 (12.0)11,204 ± 2,532 (5.0)5,028 ± 374 (2.2)
  • NOTE: Distribution study of topotecan administered i.v. (5 mg/kg) with or without the P-gp/BCRP inhibitor elacridar given orally [100 mg/kg (t = −2 h) and 50 mg/kg (t = 2 h, 6 h)] in WT, Mdr1a/b(−/−) (P-gp knockout), Bcrp1(−/−) (Bcrp1 knockout), and Mdr1a/b(−/−)Bcrp1(−/−) (compound P-gp and Bcrp1 knockout) mice (n = 25 mice per cohort). AUCplasma (ng/mL × h; mean ± SE) and AUCtissue (ng/g × h). Tissue-to-plasma AUC ratios are presented inside parentheses.

    Abbreviation: NS, not significant.

  • * Tissue-to-plasma AUC ratios of WT versus Mdr1a/b(−/−), Bcrp1(−/−) and Mdr1a/b(−/−)Bcrp1(−/−) mice.

  • Tissue-to-plasma AUC ratios within same genotype without elacridar versus with elacridar.