| http://purl.uniprot.org/citations/24194565 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/24194565 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.org/dc/terms/identifier | "doi:10.1158/1535-7163.mct-13-0541"xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "Lin F."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "Schinkel A.H."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "Ludwig M."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "Wagenaar E."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "van Tellingen O."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "van der Valk M."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "van Esch A."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "van de Steeg E."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "Iusuf D."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/author | "Elbatsh A."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/date | "2014"xsd:gYear |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/name | "Mol Cancer Ther"xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/pages | "492-503"xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/title | "OATP1A/1B transporters affect irinotecan and SN-38 pharmacokinetics and carboxylesterase expression in knockout and humanized transgenic mice."xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://purl.uniprot.org/core/volume | "13"xsd:string |
| http://purl.uniprot.org/citations/24194565 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/24194565 |
| http://purl.uniprot.org/citations/24194565 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/24194565 |
| http://purl.uniprot.org/uniprot/#_E9Q0W2-mappedCitation-24194565 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/24194565 |
| http://purl.uniprot.org/uniprot/#_A0A0N4SUN2-mappedCitation-24194565 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/24194565 |
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| http://purl.uniprot.org/uniprot/#_Q3UW56-mappedCitation-24194565 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/24194565 |
| http://purl.uniprot.org/uniprot/#_Q7TQB3-mappedCitation-24194565 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/24194565 |