OATP1A/1B transporters affect irinotecan and SN-38 pharmacokinetics and carboxylesterase expression in knockout and humanized transgenic mice
| Autor: | Ahmed M.O. Elbatsh, Olaf van Tellingen, Martin van der Valk, Marion Ludwig, Els Wagenaar, Anita van Esch, Fan Lin, Evita van de Steeg, Alfred H. Schinkel, Dilek Iusuf |
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| Rok vydání: | 2013 |
| Předmět: |
Genetically modified mouse
Cancer Research medicine.medical_specialty Organic Cation Transport Proteins Metabolite Gene Expression SN-38 Apoptosis Mice Transgenic Thymus Gland Pharmacology Organic Anion Transporters Sodium-Independent Irinotecan chemistry.chemical_compound Carboxylesterase Pharmacokinetics In vivo Internal medicine Intestine Small medicine Animals Humans Prodrugs Mice Knockout Liver-Specific Organic Anion Transporter 1 Reverse Transcriptase Polymerase Chain Reaction Up-Regulation Endocrinology Oncology chemistry Liver Area Under Curve Toxicity Camptothecin Female Carboxylic Ester Hydrolases medicine.drug |
| Zdroj: | Molecular cancer therapeutics. 13(2) |
| ISSN: | 1538-8514 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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