Article Figures & Data
Figures
- Figure 1.
Bcrp1 is expressed in mouse and primate tissues. A, Bcrp1 expression in (SCID mouse) organs that influence drug absorption and elimination. Bcrp1 is expressed at the apical face of intestinal epithelium (i), at the apical face of proximal convoluted tubules in the kidney (ii), and the liver canaliculi (iii). Probing of sections from Abcg2−/− animals (iv-vi) with the primary antibody did not produce staining. B, BCRP expression in brain tissue. Antibody specificity in human tissue was tested using formalin-fixed paraffin-embedded Saos-2 pcDNA3.1 (i) and Saos-2 BCRP (ii) cell lines. Apical BCRP localization in brain endothelium was observed in human (iii), rhesus monkey (iv), and mouse tissues (v).
- Figure 2.
Gefitinib modulates the function of multiple ABC transporters leading to increased apparent bioavailability and reduced topotecan (TPT) clearance (see Table 1). An oral dose of topotecan (2 mg/kg) was administered alone or following a gefitinib oral dose (100 mg/kg) to Abcg2+/+ and Abcg2−/− mice (A), Mdr1(a/b)+/+ and Mdr1(a/b)−/− mice (B), and SCID mice (C).
- Figure 3.
Gefitinib modulates the function of human BCRP and MDR1. A, accumulation of Hoechst 33342 dye in cells expressing human BCRP increased following incubation with gefitinib. Similarly, co-incubation with gefitinib increased accumulation of calcein in cells expressing MDR1. B, quantitative assessment of gefitinib effects from representative flow cytometry experiments. C, gefitinib abolished MDR1 resistance to vincristine. D, low intracellular accumulation in BCRP-expressing cells suggests gefitinib is a substrate at the low micromolar range but overall intracellular differences are minimal.
Tables
- Table 1.
Summary of topotecan pharmacokinetic parameters in wild-type and transporter-deficient mice treated with topotecan alone or with topotecan plus gefitinib
Parameter Treatment P Topotecan Topotecan Topotecan + gefitinib Abcg2+/+ Abcg2−/− Abcg2−/− (+/+) vs (−/−) Gefitinib vs without CL (L/h/m2) 15.4 (1.6) 11.3 (2.2) 8.3 (2.5) 0.006 0.008 Vc (L/m2) 5.75 (0.8) — — — — F 0.11 (0.02) 0.22 (0.06) 0.47 (0.11) 0.06 0.006 Kcp (h−1) 0.50 (0.12) — — — — Kpc (h−1) 0.62 (0.09) — — — — Ka (h−1) 2.35 (0.40) — — — — Mdr1(a/b)+/+ Mdr1(a/b)−/− Mdr1(a/b)−/− (+/+) vs (−/−) Gefitinib vs without CL (L/h/m2) 15.5 (0.97) 12.2 (1.5) 10.2 (1.4) 0.004 0.04 Vc (L/m2) 4.9 (0.47) — — — — F 0.21 (0.02) 0.30 (0.04) 0.50 (0.10) 0.01 0.03 Kcp (h−1) 0.32 (0.04) 1.45 (0.41) 0.29 (0.57) 0.006 0.004 Kpc (h−1) 0.68 (0.06) — — — — Ka (h−1) 2.02 (0.48) — — — — SCID SCID Gefitinib vs without CL (L/h/m2) 42.2 (4.6) 22.5 (7.2) 0.0004 Vc (L/m2) 19.2 (3.7) — — F 0.35 (0.09) 0.61 (0.14) 0.02 Kcp (h−1) 0.59 (0.19) — — Kpc (h−1) 0.18 (0.07) — — Ka (h−1) 1.43 (0.42) 4.41 (0.86) 0.00008 -
NOTE: Data are presented as mean (SE). —, no significant difference.
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Volume 66, Issue 9
