Emerging Models of Drug Metabolism, Transporters, and Toxicity

Abstract

This commentary summarizes expert mini-reviews and original research articles that have been assembled in a special issue on novel models of drug metabolism and disposition. The special issue consists of research articles or reviews on novel static or microflow based models of the intestine, liver, eye, and kidney. This issue reviews static intestinal systems like mucosal scrapings and cryopreserved intestinal enterocytes, as well as novel bioengineered or chemically engineered intestinal models derived from primary human tissue, iPSCs, enteroids, and crypts. Experts have reviewed hepatic systems like cryopermeabilized Metmax hepatocytes and longer term, hepatocyte coculture system from HmREL, yielding in vivo-like primary and secondary drug metabolite profiles. Additional liver models, including micropattern hepatocyte coculture, 3D liver spheroids, and microflow systems, applicable to the study of drug disposition and toxicology have also been reviewed. In this commentary, we have outlined expert opinions and current efforts on hepaticand nephrotoxicity models. Ocular disposition models including corneal permeability models have been included within this special issue. This commentary provides a summary of in vivo mini-reviews of the issue, which have discussed the applications and drawbacks of pig and humanized mice models of P450, UGT, and rat organic anionic transporting polypeptide 1a4. While not extensively reviewed, novel positron emissions tomography imaging-based approaches to study the distribution of xenobiotics have been highlighted. This commentary also outlines in vitro and in vivo models of drug metabolism derived from breakthrough genetic, chromosomal, and tissue engineering techniques. The commentary concludes by providing a futuristic view of the novel models discussed in this issue.

Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications

“…Drugs undergo biotransformations, and thus the optimization of the drug structure per se could be useless when significant metabolic liability, generating novel compounds (metabolites), occurs. In the last two decades, many efforts have been made to decode and predict the metabolic fate of drugs, and in silico models, − in vitro assays, and hybrid approaches (i.e., innovative assays associated with software-assisted data processing) , have been developed to identify the “soft spots” of drugs. Despite signs of progress in the field, all available ADME tools have been calibrated mainly using the chemical space of small molecules, witnessing the outstanding impact that the Lipinski rules have had in pharmaceutical research in the past.…”

Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

“…Whole cells such as primary hepatocytes, cultured hepatic mono/cocultures (e.g., with Kupffer cells) and derived cell lines (e.g., HepG2) are also used in DDI studies for estimation of multiple uptakes, metabolism, and/or efflux kinetic parameters (Zamek‐Gliszczynski et al., 2013). Novel hepatic systems such as cryopermeabilized Metmax hepatocytes and longer term hepatocyte coculture systems, micropattern hepatocyte cocultures, 3D liver spheroids, and microfluidic systems are available on the market for use in the drug disposition studies (Sawant‐Basak & Obach, 2018). As reviewed and discussed by Bale and Borenstein (2018), unlike conventional cryopreserved hepatocyte suspension assays, hepatic microfluidic coculture systems (hepatocytes with Kupffer and/or stellate cells) capture dynamic, human‐relevant behavior, and allow to study complex underlying mechanisms of nutrient transport, drug‐disease interactions, and the metabolism‐transport interplay.…”

SpheroidPicker for automated 3D cell culture manipulation using deep learning

“…However, it has been shown that the microenvironment of the in vivo tumor is different from the 2D monolayer cell cultures 2 . It has been also described that three-dimensional (3D) cell cultures are physiologically more relevant model systems for drug testing 3 and cancer research because they enable the examination of drug penetration and tumor development 4 , 5 . One of the most common 3D cell cultures is the spheroid models where the cells aggregate, produce an extracellular matrix, consequently form a sphere-like structure 6 .…”