Header

UZH-Logo

Maintenance Infos

Measurement of Hepatic ABCB1 and ABCG2 Transport Activity with [11C]Tariquidar and PET in Humans and Mice


Hernández Lozano, Irene; Bauer, Martin; Wulkersdorfer, Beatrix; Traxl, Alexander; Philippe, Cécile; Weber, Maria; Häusler, Stephanie; Stieger, Bruno; Jäger, Walter; Mairinger, Severin; Wanek, Thomas; Hacker, Marcus; Zeitlinger, Markus; Langer, Oliver (2020). Measurement of Hepatic ABCB1 and ABCG2 Transport Activity with [11C]Tariquidar and PET in Humans and Mice. Molecular Pharmaceutics, 17(1):316-326.

Abstract

P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in the canalicular membrane of hepatocytes mediate the biliary excretion of drugs and drug metabolites. To measure hepatic ABCB1 and ABCG2 activity, we performed positron emission tomography (PET) scans with the ABCB1/ABCG2 substrate [11C]tariquidar in healthy volunteers and wild-type, Abcb1a/b(−/−), Abcg2(−/−), and Abcb1a/b(−/−)Abcg2(−/−) mice without and with coadministration of unlabeled tariquidar. PET data were analyzed with a three-compartment pharmacokinetic model. [11C]Tariquidar underwent hepatobiliary excretion in both humans and mice, and tariquidar coadministration caused a significant reduction in the rate constant for the transfer of radioactivity from the liver into bile (by −74% in humans and by −62% in wild-type mice), suggesting inhibition of canalicular efflux transporter activity. Radio-thin-layer chromatography analysis revealed that the majority of radioactivity (>87%) in the mouse liver and bile was composed of unmetabolized [11C]tariquidar. PET data in transporter knockout mice revealed that both ABCB1 and ABCG2 mediated biliary excretion of [11C]tariquidar. In vitro experiments indicated that tariquidar is not a substrate of major hepatic basolateral uptake transporters (SLCO1B1, SLCO1B3, SLCO2B1, SLC22A1, and SLC22A3). Our data suggest that [11C]tariquidar can be used to measure hepatic canalicular ABCB1/ABCG2 transport activity without a confounding effect of uptake transporters.

Abstract

P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in the canalicular membrane of hepatocytes mediate the biliary excretion of drugs and drug metabolites. To measure hepatic ABCB1 and ABCG2 activity, we performed positron emission tomography (PET) scans with the ABCB1/ABCG2 substrate [11C]tariquidar in healthy volunteers and wild-type, Abcb1a/b(−/−), Abcg2(−/−), and Abcb1a/b(−/−)Abcg2(−/−) mice without and with coadministration of unlabeled tariquidar. PET data were analyzed with a three-compartment pharmacokinetic model. [11C]Tariquidar underwent hepatobiliary excretion in both humans and mice, and tariquidar coadministration caused a significant reduction in the rate constant for the transfer of radioactivity from the liver into bile (by −74% in humans and by −62% in wild-type mice), suggesting inhibition of canalicular efflux transporter activity. Radio-thin-layer chromatography analysis revealed that the majority of radioactivity (>87%) in the mouse liver and bile was composed of unmetabolized [11C]tariquidar. PET data in transporter knockout mice revealed that both ABCB1 and ABCG2 mediated biliary excretion of [11C]tariquidar. In vitro experiments indicated that tariquidar is not a substrate of major hepatic basolateral uptake transporters (SLCO1B1, SLCO1B3, SLCO2B1, SLC22A1, and SLC22A3). Our data suggest that [11C]tariquidar can be used to measure hepatic canalicular ABCB1/ABCG2 transport activity without a confounding effect of uptake transporters.

Statistics

Citations

Dimensions.ai Metrics
15 citations in Web of Science®
17 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

180 downloads since deposited on 16 Jan 2020
35 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Medicine
Life Sciences > Pharmaceutical Science
Life Sciences > Drug Discovery
Uncontrolled Keywords:Molecular Medicine, Drug Discovery, Pharmaceutical Science
Language:English
Date:6 January 2020
Deposited On:16 Jan 2020 12:15
Last Modified:22 Jun 2024 01:39
Publisher:American Chemical Society (ACS)
ISSN:1543-8384
OA Status:Green
Publisher DOI:https://doi.org/10.1021/acs.molpharmaceut.9b01060
PubMed ID:31790256
Project Information:
  • : FunderSNSF
  • : Grant ID310030_166563
  • : Project TitleRole of Membrane Lipid Environment on the Transport Acitivity of Hepatocellular Organic Anion Transporters
  • Content: Accepted Version
  • Language: English