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

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.

Assessing the Functional Redundancy between P-gp and BCRP in Controlling the Brain Distribution and Biliary Excretion of Dual Substrates with PET Imaging in Mice

“…In order to study hepatobiliary excretion of the three radiolabeled P-gp/BCRP substrates, we analyzed the PET data with a liver PK model that was slightly modified from a previously developed model [ 28 ]. Although the [ 11 C]tariquidar PET data have already been analyzed with another liver PK model [ 27 ], a re-analysis of the data was done with the modified PK model to enable a direct comparison with the other two radiotracers. In addition, integration plot analysis has previously been applied to assess the influence of P-gp and BCRP on the biliary excretion of [ 11 C]erlotinib in mice [ 16 ].…”

“…This is supported by previous studies in wild-type mice, in which the majority of radioactivity in plasma, brain, and liver after i.v. injection of [ 11 C]tariquidar, [ 11 C]erlotinib, or [ 11 C]elacridar was found to be in the form of unmetabolized radiotracer (percentage of unchanged radiotracer at 25–30 min after radiotracer injection, plasma: 78.3% ([ 11 C]tariquidar), 90.3% ([ 11 C]erlotinib), 95.8% ([ 11 C]elacridar); brain: 88.8% ([ 11 C]erlotinib), 95.4% ([ 11 C]elacridar); liver: 92.8% ([ 11 C]tariquidar), 74.8% ([ 11 C]erlotinib)) [ 14 , 27 , 32 ].…”

“…The [ 11 C]tariquidar data set has already been previously analyzed with a three-compartment model [ 27 , 28 ], which was slightly modified in this work ( Figure 1 ) and applied to all three radiotracers in order to estimate the PK parameters defining the transfer of radioactivity between the compartments. CL 1 (mL/min) represents the hepatic uptake clearance, k 2 (min −1 ) is the rate constant describing the transfer of radioactivity from liver into the sink compartment (blood), and k 3 (min −1 ) is the rate constant describing the transfer of radioactivity from liver into excreted bile.…”

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats

“…In addition, DCE–MRI contrast agents are commonly used in clinical practice, do not require specialized synthesis facilities, and are, therefore, more easily accessed than PET or SPECT tracers. 18 , 19 …”

P-Glycoprotein/ABCB1 Might Contribute to Morphine/Cisplatin-Induced Hepatotoxicity in Rats

“…2020, 88, 14 2 of 12 transporter that actively pumps its various substrates across sanctuary membranes at the expense of ATP [9]. In the liver, P-gp is expressed in the canalicular membrane of the liver, and acts as an efflux transporter for its various xenobiotic substrates from the intracellular compartment of hepatocytes to be excreted in bile [10]. MOR has been reported as one of the substrates of P-gp [11].…”