Imaging the impact of cyclosporin A and dipyridamole on P-glycoprotein (ABCB1) function at the blood-brain barrier: A [11C]-N-desmethyl-loperamide PET study in nonhuman primates

Damont, Annelaure; Goutal, Sébastien; Auvity, Sylvain; Valette, Héric; Kühnast, Bertrand; Saba, Wadad; Tournier, Nicolas

doi:10.1016/j.ejps.2016.06.005

Cited by 13 publications

(12 citation statements)

References 32 publications

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“…Cyclosporine is an inhibitor of cerebral12 and intestinal13 P‐glycoprotein. P‐glycoproteins are involved in morphine intestinal absorption14 and neurological circulation 15.…”

Section: Methodsmentioning

confidence: 99%

Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction

Bonin

Mewton

Roubille

et al. 2018

JAHA

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BackgroundMorphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior ST‐segment elevation myocardial infarction followed up for 1 year.Methods and ResultsWe used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior ST‐segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively; P=0.15). The all‐cause mortality was 5.3% in the morphine group versus 5.8% in the no‐morphine group (P=0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023±118 versus 3903±149 IU/L; P=0.52).ConclusionsIn anterior ST‐segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year.

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“…Cyclosporine is an inhibitor of cerebral12 and intestinal13 P‐glycoprotein. P‐glycoproteins are involved in morphine intestinal absorption14 and neurological circulation 15.…”

Section: Methodsmentioning

confidence: 99%

Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction

Bonin

Mewton

Roubille

et al. 2018

JAHA

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“…Racemic Luurtsema et al, 2003;Römermann et al, 2013) and which have been used to visualize P-gp function at the rodent and human BBB in various settings. These radiotracers were very useful in measuring the effects of P-gp inhibition at the BBB with inhibitors such as cyclosporine A and tariquidar (Bauer et al, 2012;Damont et al, 2016;Kreisl et al, 2015;Sasongko et al, 2005). Figure 4 shows PET data on the effect of the third-generation P-gp inhibitor tariquidar on brain distribution of (R)-[ 11 C]verapamil in rats and in humans.…”

Section: Brain Transportersmentioning

confidence: 99%

Imaging techniques to study drug transporter function in vivo

Tournier

Stieger

Langer

2018

Pharmacology & Therapeutics

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Transporter systems involved in the permeation of drugs and solutes across biological membranes are recognized as key determinants of pharmacokinetics. Typically, the action of membrane transporters on drug exposure to tissues in living organisms is inferred from invasive procedures, which cannot be applied in humans. In recent years, imaging methods have greatly progressed in terms of instruments, synthesis of novel imaging probes as well as tools for data analysis. Imaging allows pharmacokinetic parameters in different tissues and organs to be obtained in a non-invasive or minimally invasive way. The aim of this overview is to summarize the current status in the field of molecular imaging of drug transporters. The overview is focused on human studies, both for the characterization of transport systems for imaging agents as well as for the determination of drug pharmacokinetics, and makes reference to animal studies where necessary. We conclude that despite certain methodological limitations, imaging has a great potential to study transporters at work in humans and that imaging will become an important tool, not only in drug development but also in medicine. Imaging allows the mechanistic aspects of transport proteins to be studied, as well as elucidating the influence of genetic background, pathophysiological states and drug-drug interactions on the function of transporters involved in the disposition of drugs.

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“…Radiolabeled substrates or inhibitors of the ABC transporters can be used to study their function, but one of the difficulties encountered is the need for specific probes due to overlapping substrate and inhibitor affinities (Section 3.2). [ 11 C]erlotinib [249][250][251] [263][264][265] have been used to specifically visualize P-gp function because they are not transported by BCRP. To date, there is no specific PET tracer for BCRP, as the compounds developed as specific molecules, such as [ 67 Ga]Galmydar, showed no significant difference between BCRP knockout and wild-type mice or rats [266][267][268], and it would not be ideal to substrate the specific activity of P-gp from that of a P-gp/BCRP common substrate, as their function is synergic and not additive [53,98].…”

Section: Imaging Methodsmentioning

confidence: 99%

“…Among other applications, TEP has been used to asses P-gp and BCRP function and inhibition in mouse [238,253,270], rat [261,271], primate [250,264] and human [251,254] models; and it could be used for precision medicine through the evaluation of individual variability in response to CNS drugs [272]. In addition, diverse strategies have been developed to study for instance drug-drug interactions of unlabeled molecules in combination with already available tracers [246].…”

Section: Imaging Methodsmentioning

confidence: 99%

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

et al. 2019

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Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.

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Imaging the impact of cyclosporin A and dipyridamole on P-glycoprotein (ABCB1) function at the blood-brain barrier: A [11C]-N-desmethyl-loperamide PET study in nonhuman primates

Cited by 13 publications

References 32 publications

Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction

Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction

Imaging techniques to study drug transporter function in vivo

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

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