Advances in engineered human liver platforms for drug metabolism studies

Gregory H. Underhill, Salman R. Khetani

Research output: Contribution to journalArticle

Abstract

Metabolism in the liver often determines the overall clearance rates of many pharmaceuticals. Furthermore, induction or inhibition of the liver drug metabolism enzymes by perpetrator drugs can influence the metabolism of victim drugs (drug-drug interactions). Therefore, determining liver-drug interactions is critical during preclinical drug development. Unfortunately, studies in animals are often of limited value because of significant differences in the metabolic pathways of the liver across different species. To mitigate such limitations, the pharmaceutical industry uses a continuum of human liver models, ranging from microsomes to transfected cell lines and cultures of primary human hepatocytes (PHHs). Of these models, PHHs provide a balance of high-throughput testing capabilities together with a physiologically relevant cell type that exhibits all the characteristic enzymes, cofactors, and transporters. However, PHH monocultures display a rapid decline in metabolic capacity. Consequently, bioengineers have developed several tools, such as cellular microarrays, micropatterned cocultures, self-assembled and bioprinted spheroids, and perfusion devices, to enhance and stabilize PHH functions for 2 weeks. Many of these platforms have been validated for drug studies, whereas some have been adapted to include liver nonparenchymal cells that can influence hepatic drug metabolism in health and disease. Here, we focus on the design features of such platforms and their representative drug metabolism validation datasets, while discussing emerging trends. Overall, the use of engineered human liver platforms in the pharmaceutical industry has been steadily rising over the last 10 years, and we anticipate that these platforms will become an integral part of drug development with continued commercialization and validation for routine screening use.

Original languageEnglish (US)
Pages (from-to)1626-1637
Number of pages12
JournalDrug Metabolism and Disposition
Volume46
Issue number11
DOIs
StatePublished - Nov 2018

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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