Pharmacokinetics‐On‐a‐Chip: In Vitro Microphysiological Models for Emulating of Drugs ADME

Abstract

pharmacodynamics (PD), and toxicity studies, of the past century and continue to provide a wealth of knowledge and understanding of various diseases mechanism and therapy. [1][2][3] However, the use of these models in research and industrial applications has been a subject of heated debate, particularly, due to ethical matters and the increasing pressure by the animalright activists. [4] In addition, the phylogenetic difference between laboratory animals and humans may lead to drug failure during human clinical studies. [5] Furthermore, the inherent complexity of the animal's body tissue makes it difficult to interpret the physiological events that characterize the interaction of a particular organ or cells with exogenic factors. [6] In line with regulatory developments precluding the use of animal testing, human in vitro methodologies is required to replace the animal-based testes while permitting equivalent or superior prediction. [7,8] Despite many efforts, no sufficiently acceptable in vitro approaches have been developed to date, and the major gap to predict drug response in human still existed. Utilizing animal models can lead to significant insights into the complex pathophysiology of the disease. [9] However, the pathophysiology may differ between humans and animals. [10,11] Comparing to animal model-based studies, these interactions are less well understood in humans. This is a necessity considering the differences between animal and human immune responses and outcomes in preclinical models versus clinical trials. [10,11] There is consequently a real need for in vitro models of the human organs that closely mimic the physiological processes of disease development with an acceptable level of flexibility, accuracy, and reproducibility for efficient screening of potential drug candidates. Such models would increase the predictability of human response to drugs and reduce experimentation expenses and speed up the screening processes. Failing to produce safe and efficient preclinical leads and drug candidates is associated with overall low R&D efficiency and high cost. The cost of developing a new drug that gains marketing approval is estimated to be $2.6 billion (as of 2013) which includes the in vitro and in vivo animal models during the preclinical and clinical trials stages which may last several Despite many ongoing efforts across the full spectrum of pharmaceutical and biotech industries, drug development is still a costly undertaking that involves a high risk of failure during clinical trials. Animal models played vital roles in understanding the mechanism of human diseases. However, the use of these models has been a subject of heated debate, particularly due to ethical matters and the inevitable pathophysiological differences between animals and humans. Current in vitro models lack the sufficient functionality and predictivity of human pharmacokinetics and toxicity, therefore, are not capable to fully replace animal models. The recent development of microphysiological systems has shown great potentia...

Renal Hypoxic Reperfusion Injury-on-Chip Model for Studying Combinational Vitamin Therapy

“…These secretions occur under membrane transporters and require cellular barrier integrity. 26 The TEER of the RHR injury-on-chip model was evaluated as an indicator of cell−cell tight junction formation for examining the influence of RHR injury on the RPTEC monolayer. The TEER was monitored every hour from day 0 until the termination of the experiment using an in-house TEER monitoring system.…”

“…Proximal tubular cells are the primary drivers of the active tubular secretions that are vital for drug secretion and release and metabolic excretion. These secretions occur under membrane transporters and require cellular barrier integrity . The TEER of the RHR injury-on-chip model was evaluated as an indicator of cell–cell tight junction formation for examining the influence of RHR injury on the RPTEC monolayer.…”

Annual banned‐substance review: Analytical approaches in human sports drug testing 2020/2021

“…Such metabolic biotransformations were investigated regarding the GH secretagogues (GHS) capromorelin, macimorelin, and tabimorelin (Figure 1, 1 – 3 ) by Lange et al, 135 using in‐vitro and animal in‐vivo approaches. A series of metabolites was detected for each drug; however, only a rather small intersecting set was observed when considering all products found in the in vivo (rat plasma, rat urine) and in vitro (human serum, human liver microsomes) experiments, underlining the importance of studying the metabolic fate of drugs as comprehensively and close to human physiology as possible 136 . The intact drugs of capromorelin and tabimorelin were tentatively suggested as the most suitable target analytes due to their traceability in rat urine up to 36 h following a single oral dose (0.5–1 mg) of the drug.…”

Microfluidic-based in vitro thrombosis model for studying microplastics toxicity

“…The development of a toxicology platform that realistically reproduces these interactions is urgently needed to further reveal the potential risk of MP-related blood issues. 1,3,15…”

“…The development of a toxicology platform that realistically reproduces these interactions is urgently needed to further reveal the potential risk of MP-related blood issues. 1,3,15 At present, a series of studies based on cellular experiments and mouse models has been reported for the effects of MPs on the coagulation cascade system and the toxicology of cells, etc. [16][17][18][19][20][21][22][23][24][25] However, there is still a gap in the study of the effects of MPs on the highly interacting vascular system.…”