Acetaminophen absorption and metabolism in an intestine/liver microphysiological system

Marin, Talita Miguel; Indolfo, Nathalia de Carvalho; Rocco, Silvana A.; Basei, Fernanda Luisa; Carvalho, Murilo; Gonçalves, Kaliandra de Almeida; Pagani, Eduardo

doi:10.1016/j.cbi.2018.11.010

Cited by 38 publications

(40 citation statements)

References 78 publications

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“…Drug metabolism and toxicity evaluation can be improved by modelling enterohepatic circulation (circulation of drugs/metabolites between liver and small intestine) as well as first‐pass metabolism, which can be achieved by combining intestine‐ and liver‐on‐a‐chip systems 55,56 . Moreover, enterocytes with their active influx and efflux transporters and metabolic enzymes interfere with drug absorption, while absorbed compounds and their metabolites further travel to the liver through the portal vein 56,57 . These compounds and metabolites may cause damage on the level of the small intestine, as well as further on after transportation to the liver 56 .…”

Section: Multi‐organ Platforms Integrating Locmentioning

confidence: 99%

Liver microphysiological platforms for drug metabolism applications

Kulsharova

Kurmangaliyeva

2021

Cell Proliferation

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Drug development is a costly and lengthy process with low success rates. To improve the efficiency of drug development, there has been an increasing need in developing alternative methods able to eliminate toxic compounds early in the drug development pipeline. Drug metabolism plays a key role in determining the efficacy of a drug and its potential side effects. Since drug metabolism occurs mainly in the liver, liver cell‐based alternative engineering platforms have been growing in the last decade. Microphysiological liver cell‐based systems called liver‐on‐a‐chip platforms can better recapitulate the environment for human liver cells in laboratory settings and have the potential to reduce the number of animal models used in drug development by predicting the response of the liver to a drug in vitro. In this review, we discuss the liver microphysiological platforms from the perspective of drug metabolism studies. We highlight the stand‐alone liver‐on‐a‐chip platforms and multi‐organ systems integrating liver‐on‐a‐chip devices used for drug metabolism mimicry in vitro and review the state‐of‐the‐art platforms reported in the last few years. With the development of more robust and reproducible liver cell‐based microphysiological platforms, the drug development field has the potential of reducing the costs and lengths associated with currently existing drug testing methods.

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Section: Multi‐organ Platforms Integrating Locmentioning

confidence: 99%

Liver microphysiological platforms for drug metabolism applications

Kulsharova

Kurmangaliyeva

2021

Cell Proliferation

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“…Sailer et al built a gut-on-a-chip from patient-derived intestinal subepithelial myofibroblasts, which incorporated growth factors and controlled physiological conditions that showed angiogenic properties under simulated perfusion (figure 7) [105]. The gut-on-a-chip also can be found coupled with other organs, such as the liver, which allows to study the absorption and metabolism of drugs [51]. Figure 7.…”

Section: Gut-on-a-chipmentioning

confidence: 99%

“…The system developed by Rajan et al including tissues from the brain, liver, lung, heart and endothelium showed metabolizing capacity for prodrug transformation, as well as representativity of cardiac toxicity [10]. Marin et al studied acetaminophen absorption and metabolism with an intestine/liver microphysiological system demonstrating the potential of these kind of systems for pharmacokinetic profiling of drug substances [51]. The cardiotoxicity of the main compound and the metabolites was evaluated with an OoC device by Oleaga et al, who developed a model that can be used in preclinical evaluation and for chronic studies [11].…”

Section: Body-on-a-chip or Human-on-a-chip For Adme Evaluation And Preclinical Developmentmentioning

confidence: 99%

Organ-on-a-Chip systems for new drugs development

2021

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Research on alternatives to the use of animal models and cell cultures has led to the creation of organ-on-a-chip systems, in which organs and their physiological reactions to the presence of external stimuli are simulated. These systems could even replace the use of human beings as subjects for the study of drugs in clinical phases and have an impact on personalized therapies. Organ-on-a-chip technology present higher potential than traditional cell cultures for an appropriate prediction of functional impairments, appearance of adverse effects, the pharmacokinetic and toxicological profile and the efficacy of a drug. This potential is given by the possibility of placing different cell lines in a three-dimensional-arranged polymer piece and simulating and controlling specific conditions. Thus, the normal functioning of an organ, tissue, barrier, or physiological phenomenon can be simulated, as well as the interrelation between different systems. Furthermore, this alternative allows the study of physiological and pathophysiological processes. Its design combines different disciplines such as materials engineering, cell cultures, microfluidics and physiology, among others. This work presents the main considerations of OoC systems, the materials, methods and cell lines used for their design, and the conditions required for their proper functioning. Examples of applications and main challenges for the development of more robust systems are shown. This non-systematic review is intended to be a reference framework that facilitates research focused on the development of new OoC systems, as well as their use as alternatives in pharmacological, pharmacokinetic and toxicological studies.

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“…Застосування методів екстракорпоральної детоксикації, на нашу думку, не вирішує проблему детоксикації при отруєнні парацетамолом. Однак окремі з методів (гемодіафільтрація й ультрафільтрація) можуть сприяти налагодженню водно-електролітного балансу, компенсувати ацидоз, зменшити набряки та послабити прояви інтоксикації [15][16][17].…”

Section: обговоренняunclassified

Диагностика И Интенсивная Терапия Острого Гепатита, Обусловленного Парацетамолом: Клиническое Наблюдение

Markova¹,

Kurdil²,

Studzinskaya³

et al. 2021

ЕМ

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Актуальность. На сегодняшний день отравление парацетамолом является одним из наиболее распространенных и опасных видов лекарственных отравлений. В Украине количество суицидальных попыток с участием парацетамола в 2018 году выросло вдвое по сравнению с 2017 годом. Цель: исследовать динамику клинических и лабораторных показателей при отравлении парацетамолом тяжелой степени, осложненном развитием острой печеночной недостаточности, и оценить эффективность применения антидотов и средств фармакологической коррекции. Материалы и методы. Случай отравления таблетками парацетамола тяжелой степени у женщины 22 лет. Результаты. Гражданка Я., 22 лет, с суицидальной целью приняла 110 таблеток парацетамола и 10 таблеток снотворного средства. Общая доза принятого парацетамола превысила 250 мг/кг массы тела. Проведено промывание желудка и кишечника. Начата инфузионная терапия растворами кристаллоидов, глюкозы, сорбитола, натрия гидрокарбоната 4%. Назначено лечение: ацетилцистеин (АЦЦ) (140 мг/кг/день), тиоктовая кислота (20 мг/кг/день), силибинин (20 мг/кг/день), адеметионин (400 мг/день), аргинина глутамат (40%, 5,0 мл/день), дексаметазон (8 мг/день). Через 24 часа зарегистрированы высокие уровни ферментов АсАт, АлАт, гамма-глутамилтранспептидазы (ГГТП), явления коагулопатии. Изменения достигли максимальных значений через 48 часов после поступления: АсАт — 19 740 Ед/л (норма — до 32 Ед/л), АлАт — 14 800 Ед/л (норма — до 33 Ед/л), ГГТП — 157 Ед/л (норма — до 32 Ед/л); протромбиновый индекс (ПТИ) — 13,0 %, международное нормализованное отношение — 4, активированное частичное тромбопластиновое время — 48. Отмечены пожелтение склер и кожи, увеличение живота, печени, асцит, появились кровянистые выделения из влагалища, уменьшение диуреза. Назначены свежезамороженная плазма, витамин К, этамзилат, фуросемид, спиронолактон, дексаметазон, пентоксифиллин. На 5-е сутки лечения началась нормализация биохимических показателей крови, а на 16-е сутки лечения пациентка была выписана в удовлетворительном состоянии. Выводы. Проблема острых отравлений парацетамолом остается актуальной в практике врача-токсиколога. Использование антидота — АЦЦ дает положительный результат при своевременном обращении пациента за медицинской помощью. Токсический гепатит, панкреатит и почечная недостаточность — типичные осложнения тяжелого отравления парацетамолом и требуют сложного комплексного лечения. Биологическими маркерами токсического процесса являются уровни в крови АсАт, АлАт, ГГТП и ПТИ.

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Acetaminophen absorption and metabolism in an intestine/liver microphysiological system

Cited by 38 publications

References 78 publications

Liver microphysiological platforms for drug metabolism applications

Liver microphysiological platforms for drug metabolism applications

Organ-on-a-Chip systems for new drugs development

Диагностика И Интенсивная Терапия Острого Гепатита, Обусловленного Парацетамолом: Клиническое Наблюдение

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