Whole-Body Distribution and Radiation Dosimetry of <sup>11</sup>C-Elacridar and <sup>11</sup>C-Tariquidar in Humans

Bauer, Martin; Blaickner, Matthias; Philippe, Cécile; Wadsak, Wolfgang; Hacker, Marcus; Zeitlinger, Markus; Langer, Oliver

doi:10.2967/jnumed.116.175182

Cited by 10 publications

(11 citation statements)

References 15 publications

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“…injection of [ 11 C]tariquidar is very low. In healthy volunteers, approximately 2% of the injected dose was recovered from urine at the end of a 90-minute PET scan, 22 while in wild-type mice this amount was approximately 0.2%. According to the investigator's brochure, tariquidar may undergo direct 21 secretion from blood into the intestine through the gastrointestinal tract mucosa.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21] The main route of elimination of tariquidar is hepatobiliary excretion, while urinary excretion represents only a minor route. 22,23 PET with [ 11 C]tariquidar has been used to visualize ABCB1 and ABCG2 transport activity at the mouse and human blood-brain barrier (BBB). 19,20,24 We hypothesized that [ 11 C]tariquidar might be a useful probe substrate to measure the activity of ABCB1 and ABCG2 in the canalicular membrane of hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…[ 11 C]Verapamil has been the ABCB1/P-glycoprotein (P-gp) selective probe substrate most commonly used in the studies and the applicability of [ 11 C]Loperamide as well as [ 11 C]Desmethylloperamide has also been demonstrated (Syvänen and Eriksson, 2013). Probes such as [ 11 C]Elacridar and [ 11 C]Tariquidar are dual substrates of ABCB1 and ABCG2 (Syvänen and Eriksson, 2013; Bauer et al, 2016a), and [ 18 F]FCWAY is transported by ABCB1, ABCG2 and ABCC1 (Liow et al, 2016).…”

Section: Methods Of Studying Efflux Transporter Expression and Functimentioning

confidence: 99%

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

Erdő

Krajcsi

2019

Front. Aging Neurosci.

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During the last decade, several articles have reported a relationship between advanced age and changes in the integrity of the blood-brain barrier (BBB). These changes were manifested not only in the morphology and structure of the cerebral microvessels but also in the expression and function of the transporter proteins in the luminal and basolateral surfaces of the capillary endothelial cells. Age-associated downregulation of the efflux pumps ATP-binding cassette transporters (ABC transporters) resulted in increased permeability and greater brain exposure to different xenobiotics and their possible toxicity. In age-related neurodegenerative pathologies like Alzheimer’s disease (AD), the amyloid-β (Aβ) clearance decreased due to P-glycoprotein (P-gp) dysfunction, leading to higher brain exposure. In stroke, however, an enhanced P-gp function was reported in the cerebral capillaries, making it even more difficult to perform effective neuroprotective therapy in the infarcted brain area. This mini-review article focuses on the efflux functions of the transporters and receptors of the BBB in age-related brain pathologies and also in healthy aging.

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“…The carbon-11 ( 11 C)-labeled third-generation P-gp inhibitors [ 11 C]tariquidar and [ 11 C]elacridar and the tyrosine kinase inhibitor [ 11 C]erlotinib are dual P-gp and BCRP substrates [ 6 , 7 , 11 ] and have been used to assess the activity of P-gp and BCRP at the human and mouse BBB [ 7 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. All three radiotracers are predominantly excreted via the hepatobiliary route [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood–brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [11C]tariquidar, [11C]erlotinib, and [11C]elacridar to assess whether a similar functional redundancy as at the BBB exists in the liver, where both transporters mediate the biliary excretion of drugs. Wild-type, Abcb1a/b(−/−), Abcg2(−/−), and Abcb1a/b(−/−)Abcg2(−/−) mice underwent dynamic whole-body PET scans after i.v. injection of either [11C]tariquidar, [11C]erlotinib, or [11C]elacridar. Brain uptake of all three radiotracers was markedly higher in Abcb1a/b(−/−)Abcg2(−/−) mice than in wild-type mice, while only moderately changed in Abcb1a/b(−/−) and Abcg2(−/−) mice. The transfer of radioactivity from liver to excreted bile was significantly lower in Abcb1a/b(−/−)Abcg2(−/−) mice and almost unchanged in Abcb1a/b(−/−) and Abcg2(−/−) mice (with the exception of [11C]erlotinib, for which biliary excretion was also significantly reduced in Abcg2(−/−) mice). Our data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P-gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level.

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Whole-Body Distribution and Radiation Dosimetry of ¹¹C-Elacridar and ¹¹C-Tariquidar in Humans

Cited by 10 publications

References 15 publications

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

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

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

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

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Whole-Body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans

Cited by 10 publications

References 15 publications

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

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

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

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

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Whole-Body Distribution and Radiation Dosimetry of ¹¹C-Elacridar and ¹¹C-Tariquidar in Humans

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

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