Human hepatocytes: isolation, cryopreservation and applications in drug development.
The recent developments in the isolation, culturing, and cryopreservation of human hepatocytes, and the application of the cells in drug development are reviewed. Recent advances include the improvement of cryopreservation procedures to allow cell attachment, thereby extending the use of the cells to assays that requires prolong culturing such as enzyme induction studies. Applications of human hepatocytes in drug development include the evaluation of metabolic stability, metabolite profiling and identification, drug-drug interaction potential, and hepatotoxic potential. The use of intact human hepatocytes, because of the complete, undisrupted metabolic pathways and cofactors, allows the development of data more relevant to humans in vivo than tissue fractions such as human liver microsomes. Incorporation of key in vivo factors with the intact hepatocytes in vitro may help predictive human in vivo drug properties. For instance, evaluation of drug metabolism and drug-drug interactions with intact human hepatocytes in 100% human serum may eliminate the need to determine in vivo intracellular concentrations for the extrapolation of in vitro data to in vivo. Co-culturing of hepatocytes and nonhepatic primary cells from other organs in the integrated discrete multiple organ co-culture (IdMOC) may allow the evaluation of multiple organ interactions in drug metabolism and drug toxicity. In conclusion, human hepatocytes represent a critical experimental model for drug development, allowing early evaluation of human drug properties to guide the design and selection of drug candidates with a high probability of clinical success.
Li
Albert P
AP
The ADMET Group LLC and In Vitro ADMET Laboratories LLC, 15235 Shady Grove Road, Suite 303, Rockville, MD 20850, USA. lialbert@apsciences.com
D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015925:Cryopreservation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D043922:Toxicogenetics / Q000379:methods
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System