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Concise review: Current and emerging biomarkers of nephrotoxicity

Concise review: Current and emerging biomarkers of nephrotoxicity

Abstract

The kidney is a primary organ for filtration of the blood and elimination of drugs and xenobiotics. These active reabsorptive and secretory processes can result in acute kidney injury as a result of these concentrative properties. Classic measures of acute kidney injury are hampered by their ability to accurately assess function before irreversible damage has occurred. This review will discuss efforts to refine the clinical utility of standard biomarkers as well as the development of novel biomarkers of nephrotoxicity.

Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity

Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity

Abstract

The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc.) that can utilize primary liver cells from multiple species (e.g., rat and human). Compared to conventional monolayer cell culture, which typically survives for 5–7 days or less, primary rat or human hepatocytes in an MPS exhibited higher viability and improved hepatic functions, such as albumin production, expression of hepatocyte marker HNF4α and canaliculi structure, for up to 14 days. Additionally, induction of Cytochrome P450 (CYP) 1A and 3A4 in cryopreserved human hepatocytes was observed in the MPS. The acute cytotoxicity of the potent hepatotoxic and hepatocarcinogen, aflatoxin B1, was evaluated in human hepatocytes cultured in an MPS, demonstrating the utility of this model for acute hepatotoxicity assessment. These results indicate that MPS-cultured hepatocytes provide a promising approach for evaluating chemical toxicity in vitro.

Abbreviations

MPS, microphysiological system; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; BNF, beta-naphthoflavone; Rif, rifampin; EROD, ethoxyresorufin-O-deethylase; CYPs, cytochrome P450s; HNF4α, hepatocyte nuclear factor 4 alpha; MDZ
midazolam, AFB; aflatoxin B1, BSEP; bile salt export pump, MRP2, multidrug resistance-associated protein 2

Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.

Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.

Abstract

Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.