The safety of newly developed lead compounds is often prioritized over efficacy. Additionally, the efficacy of a drug in a living organism may be compromised due to either too fast or too slow metabolism. Consequently, comprehensive Absorption, Distribution, Metabolism, Excretion, and Toxicology (ADME-Tox) research becomes crucial for the development of new chemical entities.
Drug metabolism in the liver can result in either drug cleavage in the organism or the generation of toxic metabolites, jeopardizing drug discovery efforts. Therefore, research on liver models is imperative for the accurate evaluation of chemical entities. This article aims to summarize established methods for assessing drug metabolism and pharmacokinetics of small molecules in vitro.
The advancements in in vitro models for drug metabolism and pharmacokinetics are vital for enhancing the drug discovery and development process. Continued research and innovation in liver models, such as human hepatocytes and microphysiological systems, contribute significantly to the accuracy and reliability of preclinical assessments. The integration of various hepatocyte models, including Human Liver Microsomes, Pooled Suspension Human Hepatocytes, Plateable Human Hepatocytes, and Spheroid Human Hepatocytes, provides a comprehensive toolkit for addressing diverse research needs.
Human Liver Microsomes, which concentrate Cytochrome P450 (CYP) enzymes, represent one of the most robust biochemical systems capable of predicting drug clearance from the bloodstream by the liver. Their utility does not necessitate a cell biology facility and can be easily implemented at the bench. However, significant disparities exist between microsomal hepatic clearance data and in vivo findings . Dynamic effects, such as induction or inhibition, cannot be captured when using human liver microsomes. Nevertheless, these models remain a primary resource for estimating clearance in high-throughput screenings.
Human Hepatocytes maintain their status as the 'golden standard' for in vitro Drug Metabolism and Pharmacokinetics (DMPK) research. Preci offers a diverse portfolio of hepatocytes for various applications.
Pooled Suspension Human Hepatocytes serve as the 'workhorses' for short-term metabolic stability analysis, incorporating both Phase I (oxidative metabolism) and Phase II (conjugation) enzymes. Since individual donors may exhibit diverse CYP and Phase II levels, pooling is essential for assay reproducibility. Preci and Biopredic International produce pooled suspension hepatocytes to ensure scalability and reproducibility in metabolic clearance experiments.
Plateable Human Hepatocytes capable of surviving for at least a week in culture, form dense monolayers crucial for metabolite identification, CYP induction or inhibition evaluation, and efflux transporter research . Contact us to explore our repository of plateable human hepatocytes with diverse donor demographics, CYP levels, inducibility, and transporter activity.
Batch HEP187730 (Male, 71 y.o.) of Preci is suitable for metabolite ID, induction, transporter evaluation, and toxicology studies. Available as 530 vials in stock.
Spheroid Human Hepatocytes can be used for miniature experiments (2,000 cells/data point) and offer the longest viability in culture. Using the Ultra-Low Attachment well-plates and serum-free media the assays with Spheroids can last for at least 4 weeks. Some breakthrough research [3,4] studies suggest that Spheroid Hepatocyte assays are attractive models for low-clearance compound metabolism evaluation. Also, spheroids were used successfully for toxicology studies, even in the high-throughput mode 
Complex in vitro models, including microphysiological systems are gaining global attention and technical confidence. Non-parenchymal cells (NPC) can be as essential for the comprehensive liver physiology assays as hepatocytes. Many researchers use 2D/3D/MPS modalities to study the toxicology of the drugs, using the NPC. Preci is the first to offer the NPC, isogenic (from the same donor) to the human hepatocytes for more representative liver modeling as a contract service.
As we navigate the complexities of liver assays, Preci remains committed to providing tailored solutions with a focus on the quantity, quality, and diversity of human hepatocytes for ADME-Tox assays. Our commitment to offering isogenic NPC alongside human hepatocytes underscores our dedication to advancing liver modeling for more representative and predictive outcomes.
In this dynamic landscape of pharmaceutical research, the integration of cutting-edge technologies and robust in vitro models continues to propel drug development forward. At Preci, we stand ready to support your research endeavors and contribute to the ongoing evolution of drug discovery and safety assessment.
1. Williamson, B., Harlfinger, S. & McGinnity, D. F. Evaluation of the Disconnect between Hepatocyte and Microsome Intrinsic Clearance and In Vitro In Vivo Extrapolation Performance. Drug Metab. Dispos. 48, 1137–1146 (2020).
2. Li, A. P. Evaluation of Adverse Drug Properties with Cryopreserved Human Hepatocytes and the Integrated Discrete Multiple Organ Co-culture (IdMOCTM) System. Toxicol. Res. 31, 137–149 (2015).
3. Kanebratt, K. P. et al. Primary Human Hepatocyte Spheroid Model as a 3D In Vitro Platform for Metabolism Studies. J. Pharm. Sci. 110, 422–431 (2021).
4. Preiss, L. C., Lauschke, V. M., Georgi, K. & Petersson, C. Multi-Well Array Culture of Primary Human Hepatocyte Spheroids for Clearance Extrapolation of Slowly Metabolized Compounds. AAPS J. 24, 41 (2022).
5. Hiemstra, S. et al. High-throughput confocal imaging of differentiated 3D liver-like spheroid cellular stress response reporters for identification of drug-induced liver injury liability. Arch. Toxicol. 93, 2895–2911 (2019).