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15357163mct130541-sup-mct-13-0541__fig_1_to_3_and_tab_1_to_3.pdf (278.78 kB)

Supplementary Figures 1 through 3 and Supplementary Tables 1 through 3 from OATP1A/1B Transporters Affect Irinotecan and SN-38 Pharmacokinetics and Carboxylesterase Expression in Knockout and Humanized Transgenic Mice

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posted on 2023-04-03, 14:04 authored by Dilek Iusuf, Marion Ludwig, Ahmed Elbatsh, Anita van Esch, Evita van de Steeg, Els Wagenaar, Martin van der Valk, Fan Lin, Olaf van Tellingen, Alfred H. Schinkel

PDF - 278KB, Supplemental figure 1. pH equilibrium between the lactone (closed ring) form and free carboxylic acid (open) form of irinotecan and SN-38. Supplemental Figure 2. Role of Oatp1a/1b uptake transporters in small intestinal (tissue plus content) exposure of irinotecan and SN-38 after intravenous administration of irinotecan (10 mg/kg) to female wild-type and Oatp1a/1b knockout mice. Supplemental Figure 3. Role of Oatp1a/1b uptake transporters in kidney exposure of irinotecan and SN-38 after intravenous administration of irinotecan (10 mg/kg) to female wild-type and Oatp1a/1b knockout mice. Supplemental Table 1. Overview of ΔCt values of the RT-PCR analysis of expression of several esterases in liver of female wild-type, Oatp1a/1b knockout (Slco1a/1b(-/-)) and OATP1B1/1B3 humanized mice. Supplemental Table 2. Overview of ΔCt values of the RT-PCR analysis of expression of several esterases in small intestine of female wild-type, Oatp1a/1b knockout (Slco1a/1b(-/-)) and OATP1B1/1B3 humanized mice. Supplemental Table 3. Overview of ΔCt values of the RT-PCR analysis of expression of several esterases in kidney of female wild-type, Oatp1a/1b knockout (Slco1a/1b(-/-)) and OATP1B1/1B3 humanized mice.

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ARTICLE ABSTRACT

Organic anion-transporting polypeptides (OATP) mediate the hepatic uptake of many drugs, thus codetermining their clearance. Impaired hepatic clearance due to low-activity polymorphisms in human OATP1B1 may increase systemic exposure to SN-38, the active and toxic metabolite of the anticancer prodrug irinotecan. We investigated the pharmacokinetics and toxicity of irinotecan and SN-38 in Oatp1a/1b-null mice: Plasma exposure of irinotecan and SN-38 was increased 2 to 3-fold after irinotecan dosing (10 mg/kg, i.v.) compared with wild-type mice. Also, liver-to-plasma ratios were significantly reduced, suggesting impaired hepatic uptake of both compounds. After 6 daily doses of irinotecan, Oatp1a/1b-null mice suffered from increased toxicity. However, Oatp1a/1b-null mice had increased levels of carboxylesterase (Ces) enzymes, which caused higher conversion of irinotecan to SN-38 in plasma, potentially complicating pharmacokinetic analyses. Ces inhibitors blocked this increased conversion. Interestingly, liver-specific humanized OATP1B1 and OATP1B3 transgenic mice had normalized hepatic expression of Ces1 genes. While irinotecan liver-to-plasma ratios in these humanized mice were similar to those in Oatp1a/1b-null mice, SN-38 liver-to-plasma ratios returned to wild-type levels, suggesting that human OATP1B proteins mediate SN-38, but not irinotecan uptake in vivo. Upon direct administration of SN-38 (1 mg/kg, i.v.), Oatp1a/1b-null mice had increased SN-38 plasma levels, lower liver concentrations, and decreased cumulative biliary excretion of SN-38. Mouse Oatp1a/1b transporters have a role in the plasma clearance of irinotecan and SN-38, whereas human OATP1B transporters may only affect SN-38 disposition. Oatp1a/1b-null mice have increased expression and activity of Ces1 enzymes, whereas humanized mice provide a rescue of this phenotype. Mol Cancer Ther; 13(2); 492–503. ©2013 AACR.

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