title: OATP1A/1B transporters affect irinotecan and SN-38 pharmacokinetics and carboxylesterase expression in knockout and humanized transgenic mice.
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.
authors.affiliation: Corresponding Author: Alfred H. Schinkel, Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. a.schinkel@nki.nl.
authors.forename: Dilek
authors.initials: D
authors.lastname: Iusuf
authors.forename: Marion
authors.initials: M
authors.lastname: Ludwig
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elbatsh
authors.forename: Anita
authors.initials: A
authors.lastname: van Esch
authors.forename: Evita
authors.initials: E
authors.lastname: van de Steeg
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.forename: Martin
authors.initials: M
authors.lastname: van der Valk
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D018345:Mice, Knockout; D008822:Mice, Transgenic; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D002166:Camptothecin; D002265:Carboxylic Ester Hydrolases; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D011355:Prodrugs; C572127:SLCO1A1 protein, mouse; C498887:Slco1b2 protein, mouse; C545375:carboxylesterase 1, mouse