Potential application of mass spectrometry imaging in pharmacokinetic studies

Nwabufo, Chukwunonso K; Aigbogun, Omozojie P

doi:10.1080/00498254.2022.2119900

Cited by 4 publications

(3 citation statements)

References 137 publications

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“…Further investigation of SARS-CoV-2-mediated dysregulation of human pulmonary DMETs and its potential implication in controlling the safety and efficacy of promising COVID-19 drugs as well as possible unexpected adverse drug reactions in COVID-19 patients on polypharmacy is needed. Further research is required to determine the spatial distribution and disposition of promising COVID-19 drugs at the cellular level in human lung tissues, and mass spectrometry imaging may offer an appealing analytical platform to further investigate this aspects ( Nwabufo and Aigbogun, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Currently, there is no cure for COVID-19; however, drugs such as remdesivir, molnupiravir, and nirmatrelvir have shown great promise relative to other candidates ( Cascella et al, 2022 ). A major determining factor for the clinical efficacy and safety of these drugs is their ability to sufficiently distribute within the host and reach optimal therapeutic concentrations at disease target sites, particularly the lung tissue, the main organ affected by SARS-CoV-2 infection ( Nwabufo and Aigbogun, 2022 ). For example, a previous study in rats found that the plasma levels of lopinavir were greater than its lung concentrations ( Kumar et al, 2004 ), indicating that the drug may not be reaching the optimal pulmonary concentrations required to effectively eradicate SARS-CoV-2 virus.…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues

Nwabufo¹,

Hoque²,

Yip³

et al. 2023

Front. Pharmacol.

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SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit the clinical efficacy and safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Also, we assessed the role of 2 inflammatory and 4 regulatory proteins in modulating the dysregulation of DMETs in human lung tissues. We showed for the first time that SARS-CoV-2 infection dysregulates CYP3A4 and UGT1A1 at the mRNA level, as well as P-gp and MRP1 at the protein level, in Vero E6 cells and postmortem human lung tissues, respectively. We observed that at the cellular level, DMETs could potentially be dysregulated by SARS-CoV-2-associated inflammatory response and lung injury. We uncovered the pulmonary cellular localization of CYP1A2, CYP2C8, CYP2C9, and CYP2D6, as well as ENT1 and ENT2 in human lung tissues, and observed that the presence of inflammatory cells is the major driving force for the discrepancy in the localization of DMETs between COVID-19 and control human lung tissues. Because alveolar epithelial cells and lymphocytes are both sites of SARS-CoV-2 infection and localization of DMETs, we recommend further investigation of the pulmonary pharmacokinetic profile of current COVID-19 drug dosing regimen to improve clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues

Nwabufo¹,

Hoque²,

Yip³

et al. 2023

Front. Pharmacol.

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“…Elimination usually occurs in two main ways: renal elimination, in which the drug is excreted from the circulation by renal filtration, and hepatic elimination, in which molecules are metabolized in the liver and removed by the biliary tract. Therefore, pharmacokinetics is a tool that benefits the development of new formulations and new therapeutic systems, demonstrating the adequate biopharmaceutical behavior of drugs and molecules for determined therapeutic objectives(Madden & Thompson, 2022;Nwabufo & Aigbogun, 2022;Shargel & Yu, 2016).Radiolabeling and molecular imaging allow the evaluation of biological and chemical processes at the cellular level in the organism, unlike conventional imaging techniques such as computed tomography (CT), x-rays, and ultrasound, which offer pictures of the body physical structure. Fundamentally, molecular imaging enables visualization and localization of biochemical processes in the body through specific targets at the anatomical level Du et al, 2019;…”

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confidence: 99%

Evaluation of MCP anticancer activity using molecular imaging

Silva

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MCP is a polysaccharide found abundantly in the plant's primary wall and shows activity in several areas of the food industry and nutrition, serving in food production, improving intestinal flow, reducing cholesterol, and being an important nutritional compound. MCP can also act as an anti-tumorigenic molecule in several types of tumors, in addition to avoiding chemoresistance, modulating the immune system, and preventing renal disease caused by radiotherapy and chemotherapy in cancer treatments. This study was divided into three main parts. In the first part, a review was carried out to study the biological activity of MCP and its contribution to cancer therapy, demonstrating treatment doses, types of MCP used, and experimental design, providing a critical view of the exposed data and its relationship with galectin-3 and other theories regarding its mechanisms. In the second part, we radiolabeled MCP with 99m Tc and verified the biodistribution and pharmacokinetics of MCP-99m Tc orally and intravenously (IV) administrated. First, the structure and monosaccharide composition of MCP were studied, and it was demonstrated that there is a diversity of monosaccharides and molecular weights within the MCP structure and that MCP30 and MCP3 fractions are rich in galactose. Next, we studied the inhibition and binding affinity of MCP for galectin-3 and demonstrated that MCP partially binds Gal-3 and that MCP3 shows an inhibition capacity at a concentration of 25 mg/ml. We radiolabeled MCP with 99m Tc and verified its stability in saline in different pH, plasma, and in vivo. MCP-99m Tc has a low gastrointestinal absorption (5.27x10-6 % total radioactivity counts) and gastrointestinal elimination when administered via oral and renal and hepatobiliary elimination when administered via IV. Finally, the blood compartment distribution assay showed that MCP-99m Tc has a high affinity for plasma proteins and blood cells in C57BL/6 Lgals3 +/+ mice, and this affinity was partially lost when galectin-3 was deleted in C57BL/6 Lgals3 -/mice.The pharmacokinetic assay showed that MCP-99m Tc elimination speed was greater in the C57BL/6 Lgals3 -/mice than in the C57BL/6 Lgals3 +/+ , indicating that a lack of galectin-3 increases MCP elimination. In the third part, we analyzed the behavior of MCP-99m Tc in 8 animals with SKOV-3 and MKN45 tumors using molecular imaging. First, we demonstrated that cell binding and internalization of MCP were only partially influenced by Galectin-3 expression in vitro using SKOV-3 scrambled and SKOV-3 shRNAGal3 cells (knockdown of Gal-3 expression). Next, we showed that MCP (20 mg/kg) exhibited anticancer activity in a SKOV-3 cell tumor xenograft model, reducing tumor growth by 48.5% and tumor weight by 50% when administered intravenously; however, oral administration of MCP (200 mg/kg) did not show an anticancer effect. Subsequently, we demonstrated that MCP-99m Tc reached the tumor and bound to regions of necrosis in the SKOV-3 cell tumor xenograft model when administered intravenously. Finally, we demonstr...

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