Breast Cancer Resistance Protein and P-Glycoprotein Influence In Vivo Disposition of <sup>11</sup>C-Erlotinib

Traxl, Alexander; Wanek, Thomas; Mairinger, Severin; Stanek, Johann; Filip, Thomas; Sauberer, Michael; Müller, Markus; Kuntner, Claudia; Langer, Oliver

doi:10.2967/jnumed.115.161273

Cited by 53 publications

(107 citation statements)

References 24 publications

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“…The most important finding of our study is that ABCB1/ABCG2 inhibition with elacridar can be achieved at the nonhuman primate BBB, resulting in an increase in brain distribution of 11 C-erlotinib (3.5-fold increase in brain V T ) remarkably similar to that in rodents (3.4-fold increase in brain-to-plasma concentration ratio at 25 min after radiotracer injection) (16). On the basis of earlier findings that the transporter inhibitory effect of elacridar at the BBB is rapidly reversible (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 52%

“…Erlotinib can be straightforwardly labeled with 11 C (15). Our previous study showed that the brain distribution of 11 C-erlotinib in mice is restricted by Abcb1a and Abcg2 and that radiolabeled metabolites of 11 C-erlotinib are not taken up by the brain (16). As compared with wild-type mice, distributional clearance of 11 C-erlotinib to the brain was 4.6-fold higher in Abcb1a/b (2/2) Abcg2 (2/2) mice, 5.3-fold higher in elacridarpretreated wild-type mice, and 4.5-fold higher in high-dose erlotinibpretreated wild-type mice, suggesting that both elacridar and high-dose erlotinib can inhibit Abcb1a-and Abcg2-mediated transport of 11 Cerlotinib at the mouse BBB (16).…”

Section: Discussionmentioning

confidence: 99%

“…Baseline 11 C-erlotinib kinetics (n 5 4) were compared with those obtained using infusion of high-dose erlotinib at a dose of 10 mg/ kg/h (n 5 4) and using infusion of elacridar at a dose of 12 mg/kg/h (n 5 3). The administered dose of erlotinib was based on previous experiments in rodents (16). The administered dose of elacridar was based on the maximal possible solubility of the compound.…”

Section: Experimental Conditionsmentioning

confidence: 99%

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Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood–Brain Barrier: A PET Study on Nonhuman Primates

Tournier¹,

Goutal²,

Auvity³

et al. 2016

J Nucl Med

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The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) because of efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), thereby limiting its utility in the treatment of non-small cell lung cancer metastases in the brain. Pharmacologic strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear whether these can be translated to humans given the pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ ABCG2 inhibitors to enhance brain distribution of 11 C-erlotinib in nonhuman primates as a model of the human BBB. Methods: Papio anubis baboons underwent PET scans of the brain after intravenous injection of 11 C-erlotinib under baseline conditions (n 5 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n 5 4) or elacridar (12 mg/kg/h, n 5 3). Results: Under baseline conditions, 11 C-erlotinib distribution to the brain (total volume of distribution [V T ], 0.22 6 0.015 mL/cm 3 ) was markedly lower than its distribution to muscle tissue surrounding the skull (V T , 0.86 6 0.10 mL/cm 3 ). Elacridar infusion resulted in a 3.5 6 0.9-fold increase in 11 C-erlotinib distribution to the brain (V T , 0.81 6 0.21 mL/cm 3 , P , 0.01), reaching levels comparable to those in muscle tissue, without changing 11 Cerlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, 11 C-erlotinib brain distribution was also significantly (1.7 6 0.2-fold) increased (V T , 0.38 6 0.033 mL/cm 3 , P , 0.05), with a concomitant increase in 11 C-erlotinib plasma exposure. Conclusion: We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of 11 C-erlotinib. For patients with brain tumors, such inhibition protocols may ultimately be applied to create more effective treatments using drugs that undergo efflux transport at the BBB.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Experimental Conditionsmentioning

confidence: 99%

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Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood–Brain Barrier: A PET Study on Nonhuman Primates

Tournier¹,

Goutal²,

Auvity³

et al. 2016

J Nucl Med

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“…These specific PET radiotracers have shown that P-gp restricts the brain uptake (K 1 ; influx rate constant) of its substrates, thus limiting their exposure to the brain (6). However, it was recently suggested that microdose studies may not reflect the impact of transporters on drug brain kinetics in the pharmacologic situation (7).…”

mentioning

confidence: 99%

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Pottier¹,

Marie²,

Goutal³

et al. 2015

J Nucl Med

105

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The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used 11 C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. Methods: 11 C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. 11 C-metoclopramide brain kinetics were compared using PET in rats (n 5 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The 11 C-metoclopramide brain distribution (V T based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis. Results: 11 C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline 11 C-metoclopramide brain kinetics (V T 5 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm −3 using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose 11 C-metoclopramide V T (7.80 ± 1.43 mL⋅cm −3 ) with a 4.4-fold increase in K 1 (influx rate constant) and a 2.3-fold increase in binding potential (k 3 /k 4 ) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (V T 5 6.28 ± 0.48 mL⋅cm −3 ) with a 2.0-fold increase in K 1 and a 2.2-fold decrease in k 2 (efflux rate), with no significant impact on binding potential. In this situation, only parent 11 C-metoclopramide could be detected in the brains of P-gp-inhibited rats. Conclusion: 11 C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.

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“…Several of these (Table 2) are carbon-11 versions of small molecule drugs or drug metabolites which are known liver transporter substrates (e.g., erlotinib [49]; metformin [50], rosuvastatin [51], dehydropravastatin [52], telmisartan [53], and celecoxib metabolite [54]). 11 C-labeled bile acid derivatives have also been synthesised, such as [ 11 C]cholylsarcosine [55][56][57]; these have been used to investigate the kinetics of hepatobiliary tracer uptake and secretion in healthy pigs and humans in vivo, and to quantify perturbations that occur in patients with cholestasis.…”

Section: Petmentioning

confidence: 99%

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

Kenna

Waterton

Baudy

et al. 2018

Methods in Pharmacology and Toxicology

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Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and druginduced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug-drug interactions mediated via hepatobiliary transporter perturbation.

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Breast Cancer Resistance Protein and P-Glycoprotein Influence In Vivo Disposition of ¹¹C-Erlotinib

Cited by 53 publications

References 24 publications

Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood–Brain Barrier: A PET Study on Nonhuman Primates

Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood–Brain Barrier: A PET Study on Nonhuman Primates

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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Breast Cancer Resistance Protein and P-Glycoprotein Influence In Vivo Disposition of 11C-Erlotinib

Cited by 53 publications

References 24 publications

Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood–Brain Barrier: A PET Study on Nonhuman Primates

Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood–Brain Barrier: A PET Study on Nonhuman Primates

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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Breast Cancer Resistance Protein and P-Glycoprotein Influence In Vivo Disposition of ¹¹C-Erlotinib