The use of human hepatocytes to investigate drug metabolism and CYP enzyme induction.
Over the past two decades, attrition of new drug candidates which entered into development increased strongly mainly due to sub-optimal ADME profiles. Major problems were linked to poor metabolic stability and drug-drug interactions linked to inhibition or induction of metabolism. Since most small molecule (MW below 1000) drugs are cleared from the body by the liver, primary cultures of human hepatocytes became the most predictive and widely used in vitro model for drug metabolism studies as well as enzyme induction. For this purpose, well-established and robust in vitro assays for the measurement of cell viability, metabolic activity, and cytochrome P450 (CYP) mRNA expression levels are needed to characterize the quality of the isolated and/or cryopreserved hepatocytes used to perform such studies.
Klieber
Sylvie
S
Discovery Metabolism and Pharmacokinetics Safety, Sanofi-Aventis Recherche, Montpellier, France.
Torreilles
François
F
Guillou
François
F
Fabre
Gérard
G
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015925:Cryopreservation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System