Evaluating drug metabolism and drug-drug interactions in a microscale model of hu

DESCRIPTION (provided by applicant): Liver toxicity is the leading cause of pre-launch and post-market attrition of pharmaceutical compounds (i.e. Rezulin, Prexige). Significant species-specific differences in organ functions now necessitate supplementatio n of animal data with assays designed to assess human responses to drugs. Adherent cultures of primary human hepatocytes are considered to be the gold standard for evaluating preclinical drug metabolism, enzyme induction, and liver-specific toxicity. Howev er, hepatocytes display a rapid (hours) decline in liver-specific functions under conventional culture conditions. Recently, a robust model of human liver tissue has been developed with optimized microscale architecture in an industry-standard multiwell fo rmat that retains liver-specific functions for 4-6 weeks in vitro. Hepatocytes in this microscale platform secrete liver- specific products, display functional CYP450 and conjugation enzymes, secrete molecules into the bile canaliculi, and maintain high le vels of expression of liver-specific genes relevant for evaluating drug disposition. The primary objective of this Small Business Innovation Research (SBIR) Phase I project is to assess the utility of microscale tissues for evaluating drug metabolism and d rug-drug interactions in vitro with better clinical predictivity than that afforded by conventional, declining cultures. In particular, the time course of un-induced (baseline) activities of a broad range of Phase I and II enzymes will first be characteriz ed in microscale tissues to determine the optimal time window for drug metabolism applications. Then, the utility of microscale tissues for evaluating time-dependent modulation of Phase I, II, and III transcripts and protein activities by pharmaceutical co mpounds will be evaluated towards screening drug-drug interactions in drug development. Lastly, the utility of microscale liver tissues to predict in vivo metabolic clearance and identify all major and minor metabolites better than conventional systems wil l be explored. The results of this SBIR feasibility study will enable the small business to form strategic partnerships with major pharmaceutical companies towards dissemination of microscale human liver tissues into the marketplace. In the future, microsc ale liver tissues may be used to eliminate problematic compounds much earlier in drug development towards substantially reducing development costs ( 1 billion per successfully marketed drug), increasing the likelihood of clinical success, and limiting pati ent exposure to unsafe drugs. Microscale human liver tissues may also enable the investigation of mechanisms of drug action, allow identification of new biomarkers, and enable studies to assess the risk associated with exposure to mixtures of drugs. PUBLIC HEALTH RELEVANCE: Toxicity to the liver is the leading cause of drug withdrawals (i.e. Rezulin, Prexige) from the marketplace by regulatory agencies. The studies proposed in this SBIR Phase I project can establish utility of microscale human liver tissues for evaluating liver-specific metabolism of candidate drugs in drug development, and significantly more clinically predictive than allowed in existing conventional model systems. Therefore, in the future, microscale human liver tissues may eliminate probl ematic compounds much earlier in the drug development pipeline towards reducing patient exposure to unsafe drugs in clinical trials and in the marketplace.