Autoradiography techniques and quantification of drug distribution

Solon, Eric

doi:10.1007/s00441-014-2093-4

Cited by 61 publications

(66 citation statements)

References 42 publications

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“…More experiments employing “inert” compounds (such as oxantel pamoate, which do almost not leave the compartment of application and seems not to be metabolized) might be beneficial for further studies to exclude bias by ubiquitous presence and drug elimination. Furthermore, autoradiographic techniques (Solon, 2015) or imaging mass spectrometry (Karlsson and Hanrieder, 2016) might be employed to trace drug entry into the worm and distribution within the worm. Comparison of oral and intravenous application of such compounds might be valuable to elucidate the distribution, delivery to the target parasite and the resulting efficacy.…”

Section: Resultsmentioning

confidence: 99%

Exposure of Heligmosomoides polygyrus and Trichuris muris to albendazole, albendazole sulfoxide, mebendazole and oxantel pamoate in vitro and in vivo to elucidate the pathway of drug entry into these gastrointestinal nematodes

Cowan

Meier

Neodo

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Millions of people are treated with anthelmintics to control soil-transmitted helminth infections; yet, drug distribution in the plasma and gastrointestinal tract compartments and the pathway of drug uptake into gastrointestinal nematodes responsible for the pharmacological effect are unknown. We assessed the distribution and uptake of albendazole, albendazole sulfoxide, albendazole sulfone in the hookworm Heligmosomoides polygyrus in vitro and in vivo as well as the distribution and uptake of albendazole, mebendazole, and oxantel pamoate in the whipworm Trichuris muris in vitro and in vivo. Oral and intraperitoneal treatments (100 mg/kg) were studied. Drug quantities in helminths and host compartments (stomach, the contents and mucosa of the small and large intestine, and the plasma) were determined using HPLC-UV/vis and anthelmintic activities were recorded using phenotypic readout. The influence of 1-aminobenzotriazole (ABT), an irreversible and unspecific cytochrome P450 inhibitor, on albendazole disposition in mice harboring H. polygyrus was evaluated. In vivo, albendazole was found in quantities up to 10 nmol per ten H. polygyrus and up to 31 nmol per ten T. muris. ABT did not change the levels of albendazole or its metabolites in the plasma of mice harboring H. polygyrus or in H. polygyrus, whereas drug levels in the gastrointestinal tract of host mice doubled. Mebendazole and oxantel pamoate quantities per ten T. muris were as high as 21 nmol and 34 nmol, respectively. Albendazole revealed a very dynamic distribution and high rate of metabolism, hence, H. polygyrus and T. muris are exposed to albendazole and both metabolites via multiple pathways. Diffusion through the cuticle seems to be the crucial pathway of oxantel pamoate uptake into T. muris, and likely also for mebendazole. No relationship between concentrations measured in helminths and concentrations in plasma, intestinal content and mucosa of mice, or drug efficacy was noted for any of the drugs studied.

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Section: Resultsmentioning

confidence: 99%

Exposure of Heligmosomoides polygyrus and Trichuris muris to albendazole, albendazole sulfoxide, mebendazole and oxantel pamoate in vitro and in vivo to elucidate the pathway of drug entry into these gastrointestinal nematodes

Cowan

Meier

Neodo

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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“…Pretreatment of animals with cold iodine may help to limit this issue. For all these reasons, quantitative studies with 125 I radioactivity require careful considerations and should be considered as a semi‐quantitative technique …”

Section: General Considerationsmentioning

confidence: 99%

Autoradioluminography, a powerful and reliable tool for drug development: Accelera's experience

Marzorati¹,

Messina²,

Ghiglieri³

2019

Labelled Comp Radiopharmac

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A deeper understanding of the pharmacokinetic and pharmacodynamic properties of a drug candidate is a pivotal component of drug discovery and development. Autoradiography is an excellent technique allowing exploiting the advantages of the use of radioisotopes in the drug disscovery field. The introduction of phosphor imaging technology has revolutionized the handling of drug distribution studies providing high‐resolution images. Specifically, quantitative whole‐body autoradioluminography is employed for preclinical study where the aim is to obtain information about the route of elimination and tissue distribution of a drug candidate. Autoradioluminography is also the technique of choice pursued to deal with all the issue that it is possible to encounter in all stage of drug development (ie, site‐specific drug localization and retention, drug‐drug interactions, penetration into specific target, specific tissue binding, crossing of brain blood barrier, and placental transfer). The purpose of this review is to give a picture of how autoradiography is employed in our laboratory as a key tool for advances in the assessment of the drug disposition and to validate new experimental models.

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“…It is an efficient, high-resolution technique for quantitative localization of radioactivity in thin slices taken from brain, peripheral organs, solid tumors or, in the case of a small rodent, even the whole body [173]. The present context will be limited to detection of receptor distributions in brain, which was pioneered by Michael Kuhar and colleagues [13,14].…”

Section: Preclinical Imagingmentioning

confidence: 99%

Tactics for preclinical validation of receptor-binding radiotracers

Lever

Fan

Lever

2017

Nuclear Medicine and Biology

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Introduction Aspects of radiopharmaceutical development are illustrated through preclinical studies of [125I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA- BF-PE-PIPZE), a radioligand for sigma-1 (σ1) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [125I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA-DM-PE-PIPZE). Methods Syntheses of E-IA-BF-PE-PIPZE and [125I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ1 sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers. Results E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ1 receptors (Ki = 0.43 ± 0.03 nM, σ2 / σ1 = 173). [125I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (koff) and association (kon) rate constants, along with a measured Kd of 0.24 ± 0.01 nM and Bmax of 472 ± 13 fmol / mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, > 6% injected dose / g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%). Conclusions Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ1 receptors by 16-fold. While high specific binding to σ1 receptors was observed for both radioligands in vivo, [125I]-E-IA-BF-PE-PIPZE displayed much slower clearance kinetics than [125I]-E-IA-DM-PE-PIPZE. Thus, minor structural modifications of σ1 receptor radioligands lead to major differences in binding properties in vitro and in vivo.

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Autoradiography techniques and quantification of drug distribution

Cited by 61 publications

References 42 publications

Exposure of Heligmosomoides polygyrus and Trichuris muris to albendazole, albendazole sulfoxide, mebendazole and oxantel pamoate in vitro and in vivo to elucidate the pathway of drug entry into these gastrointestinal nematodes

Exposure of Heligmosomoides polygyrus and Trichuris muris to albendazole, albendazole sulfoxide, mebendazole and oxantel pamoate in vitro and in vivo to elucidate the pathway of drug entry into these gastrointestinal nematodes

Autoradioluminography, a powerful and reliable tool for drug development: Accelera's experience

Tactics for preclinical validation of receptor-binding radiotracers

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