David W Hein

Title: Pharmacogenomic-guided therapy: Insights from n-acetyltransferase 2 genetic polymorphism

Abstract:

Recent investigations more clearly define the effects of N-acetyltransferase 2 (NAT2) haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects.  Several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole) have been identified for which NAT2 phenotype-guided therapy may be important.  The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for NAT2 phenotype-dependent dosing strategies.  Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype.  Incorporation of more robust NAT2 genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.

Audience Take Away Notes :

• The effects of the N-acetylation polymorphism on metabolism, efficacy, and/or toxicity of numerous drugs will be described
• Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype.
• Point of care testing for NAT2 phenotype/genotype and providing dose guidance could improve safety and efficacy of isoniazid for tuberculosis prevention and treatment.  
• More robust methods for assessing N-acetylation genotype and/or phenotype should lead to further advancements in health outcomes and cost benefits.

Biography:

Dr. Hein serves as Peter K. Knoefel Endowed Chair, Professor and Chair of the Department of Pharmacology & Toxicology, and Distinguished University Scholar at the University of Louisville (USA). Dr. Hein’s research program has been funded since 1983 by grants and contracts from the National Institutes of Health and other federal and private foundations and industry. He has coauthored over 275 publications with over 17,000 citations (h-index=67).  He has presented about 150 invited research seminars in Australia, Austria, Canada, China, Czech Republic, Egypt, France, Germany, Greece, Italy, Norway, Switzerland, the United Kingdom and across the USA.