Ibogaine labeling with 99mTc-tricarbonyl: Synthesis and transport at the mouse blood–brain barrier

Tournier, Nicolas; André, Pascal; Blondeel, Sandy; Rizzo-Padoin, N.; d'Hardemarre, Amaury du Moulinet; Declèves, Xavier; Scherrmann, Jean‐Michel; Cisternino, Salvatore

doi:10.1002/jps.21771

Cited by 11 publications

(4 citation statements)

References 30 publications

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“…The P-gp-and BCRP-mediated transport of SPECT radiopharmaceuticals such as 99m Tc-sestamibi, 99m Tc-tetrofosmin, 99m Tc-hexamethyl-propyleneamine oxime, and 123 I-metaiodobenzylguanidine has been studied in vitro (27,28). However, most studies on the P-gp-mediated transport of …”

Section: Discussionmentioning

confidence: 99%

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

Tournier¹,

Valette²,

Peyronneau³

et al. 2011

J Nucl Med

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Radiolabeled compounds used for brain imaging with PET must readily cross the blood-brain barrier (BBB) to reach their target. Efflux transporters at the BBB-P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP)-could limit their uptake by the brain. The assays were performed using the nonradioactive form of each compound (ultraviolet high-performance liquid chromatography analysis) and, when available, the 18 F-labeled analogs (g-counting). Results: Befloxatone appeared to be transported solely by BCRP. Loperamide, verapamil, and diprenorphine were the only P-gp substrates. Other ligands were transported by neither P-gp nor BCRP. Conclusion: The present method can readily be used to screen new-compound transport by Pgp or BCRP, even before any radiolabeling. Compounds that were previously thought to be transported by P-gp in rodents, such as p-MPPF, WAY-100635, and flumazenil, cannot be considered substrates of human P-gp. The impact of BCRP and P-gp at the BBB on the transport of befloxatone and diprenorphine in vivo remains to be evaluated with PET.

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Section: Discussionmentioning

confidence: 99%

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

Tournier¹,

Valette²,

Peyronneau³

et al. 2011

J Nucl Med

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“…Still, Tournier et al (2009) evaluated the ABCB1-and ABCG2-mediated transport of different compounds including ibogaine labeled with (99 m)Tc-tricarbonyl, in human (h)ABCB1-and hABCG2-transfected HEK293 cells, with or without specific inhibitors, and in situ by a mouse brain perfusion technique. The in vitro transport of ibogaine labeled with (99 m)Tc-tricarbonyl was not influenced by hABCB1or hABCG2, and they also observed that ABCB1-and ABCG2mediated efflux did not reduce the brain uptake of the radiolabeled ibogaine (Tournier et al, 2009). However, the authors used ibogaine modified with a tricarbonyl core and not the native compound, making it more challenging to compare these findings with ours.…”

Section: Discussionmentioning

confidence: 99%

Drug Transporters ABCB1 (P-gp) and OATP, but not Drug-Metabolizing Enzyme CYP3A4, Affect the Pharmacokinetics of the Psychoactive Alkaloid Ibogaine and its Metabolites

Martins

Heydari

et al. 2022

Front. Pharmacol.

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The psychedelic alkaloid ibogaine is increasingly used as an oral treatment for substance use disorders, despite being unlicensed in most countries and having reported adverse events. Using wild-type and genetically modified mice, we investigated the impact of mouse (m)Abcb1a/1b and Abcg2 drug efflux transporters, human and mouse OATP drug uptake transporters, and the CYP3A drug-metabolizing complex on the pharmacokinetics of ibogaine and its main metabolites. Following oral ibogaine administration (10 mg/kg) to mice, we observed a rapid and extensive conversion of ibogaine to noribogaine (active metabolite) and noribogaine glucuronide. Mouse Abcb1a/1b, in combination with mAbcg2, modestly restricted the systemic exposure (plasma AUC) and peak plasma concentration (Cmax) of ibogaine. Accordingly, we found a ∼2-fold decrease in the relative recovery of ibogaine in the small intestine with fecal content in the absence of both transporters compared to the wild-type situation. Ibogaine presented good intrinsic brain penetration even in wild-type mice (brain-to-plasma ratio of 3.4). However, this was further increased by 1.5-fold in Abcb1a/1b;Abcg2−/− mice, but not in Abcg2−/− mice, revealing a stronger effect of mAbcb1a/1b in restricting ibogaine brain penetration. The studied human OATP transporters showed no major impact on ibogaine plasma and tissue disposition, but the mOatp1a/1b proteins modestly affected the plasma exposure of ibogaine metabolites and the tissue disposition of noribogaine glucuronide. No considerable role of mouse Cyp3a knockout or transgenic human CYP3A4 overexpression was observed in the pharmacokinetics of ibogaine and its metabolites. In summary, ABCB1, in combination with ABCG2, limits the oral availability of ibogaine, possibly by mediating its hepatobiliary and/or direct intestinal excretion. Moreover, ABCB1 restricts ibogaine brain penetration. Variation in ABCB1/ABCG2 activity due to genetic variation and/or pharmacologic inhibition might therefore affect ibogaine exposure in patients, but only to a limited extent. The insignificant impact of human CYP3A4 and OATP1B1/1B3 transporters may be clinically advantageous for ibogaine and noribogaine use, as it decreases the risks of undesirable drug interactions or interindividual variation related to CYP3A4 and/or OATP activity.

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“…99m Tc is a radionuclide that requires forming an organic coordination complex, limiting the possibility to radiolabel substrates without dramatic changes in their chemical and physicochemical properties. 22 However, 99m Tc allows for easy and kit-based preparation of radiopharmaceutical agents for human use and often provides suitable metabolic stability in vivo. Several other radionuclides are eligible to SPECT, including iodine-123 or indium-111.…”

Section: Imaging Probes For Spectmentioning

confidence: 99%

Imaging Probes and Modalities for the Study of Solute Carrier O (SLCO)-Transport Function In Vivo

Marie

Cisternino

Buvat

et al. 2017

Journal of Pharmaceutical Sciences

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Transporters of the solute carrier O (SLCO) family, former organic anion-transporting polypeptides, are now recognized as key players in pharmacokinetics. Imaging is increasingly regarded as a relevant method to elucidate and decipher the intrinsic role of SLCO in controlling drug disposition in plasma and tissues. Current research in this representative field of translational research is based on different imaging modalities including nuclear imaging, such as single-photon emission computed tomography or positron emission tomography, and magnetic resonance imaging. Imaging modalities can be compared in terms of sensitivity, quantitative properties, spatial resolution, variety of ligands, and radiation exposure. All these approaches rely on the use of SLCO substrates that are detected using corresponding modalities. The present review aims at reporting and comparing the imaging probes that have been proposed to study SLCO-transport function, in terms of in vitro specificity, in vivo behavior, and clinical validation.

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Ibogaine labeling with 99mTc-tricarbonyl: Synthesis and transport at the mouse blood–brain barrier

Cited by 11 publications

References 30 publications

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

Drug Transporters ABCB1 (P-gp) and OATP, but not Drug-Metabolizing Enzyme CYP3A4, Affect the Pharmacokinetics of the Psychoactive Alkaloid Ibogaine and its Metabolites

Imaging Probes and Modalities for the Study of Solute Carrier O (SLCO)-Transport Function In Vivo

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