Biotransformation and bioactivation reactions – 2018 literature highlights

Abstract

In the past three decades, ADME sciences have become an integral component of the drug discovery and development process. At the same time, the field has continued to evolve, thus, requiring ADME scientists to be knowledgeable of and engage with diverse aspects of drug assessment: from pharmacology to toxicology, and from in silico modeling to in vitro models and finally in vivo models. Progress in this field requires deliberate exposure to different aspects of ADME; however, this task can seem daunting in the current age of mass information. We hope this review provides a focused and brief summary of a wide array of critical advances over the past year and explains the relevance of this research (Table 1). We divided the articles into categories of (1) drug optimization, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation.

This annual review is the fourth of its kind (Baillie et al. 2016; Khojasteh et al. 2017, 2018). We have followed the same format we used in previous years in terms of the selection of articles and the authoring of each section. This effort in itself also continues to evolve. I am pleased that Rietjens, Miller, and Mitra have again contributed to this annual review. We would like to welcome Namandjé N. Bumpus, James P. Driscoll, and Donglu Zhang as authors for this year’s issue. We strive to maintain a balance of authors from academic and industry settings.

We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review.

Cyrus Khojasteh, on behalf of the authors.

Additional information

Notes on contributors

S. Cyrus Khojasteh

S. Cyrus Khojasteh heads the Biotransformation Function at Genentech (South San Francisco). His research focuses on the mechanisms of biotransformation in drug discovery and development, with a particular interest in mechanisms of biotransformation as they relate to small molecules and a growing focus on macrocyclic peptides and drug payloads of antibody drug conjugates. Cyrus received his B.S. from the University of California at Berkeley and his Ph.D. in Medicinal Chemistry from the University of Washington under the direction of Dr. Sidney D. Nelson.

Namandjé N. Bumpus

Namandjé N. Bumpus is an associate professor in the Department of Medicine and the Department of Pharmacology and Molecular Sciences at the Johns Hopkins University School of Medicine. She also serves as associate dean for basic research. Bumpus earned a PhD in pharmacology at the University of Michigan under the mentorship of Dr. Paul F. Hollenberg. She then went on to complete postdoctoral training at The Scripps Research Institute in La Jolla, CA in the laboratory of Dr. Eric F. Johnson. Her research focuses on understanding the mechanisms of anti-HIV drug metabolism and the contribution of drug metabolism to HIV treatment and HIV pre-exposure prophylaxis outcomes.

James P. Driscoll

James P. Driscoll is an accomplished Scientist and Project Leader in the Drug Metabolism and Pharmacokinetics department at MyoKardia, Inc, a clinical stage biopharmaceutical company focused on genetic heart disease. He has over 17 years of industry experience with Pfizer, Genentech, Theravance and MyoKardia. His expertise includes reactive metabolite identification, drug metabolism, and bioanalysis of small molecules. His responsibilities include driving early stage projects forward by identifying structure activity relationships, avoiding off-target toxicity, interrogating potential new targets in drug discovery, and leading a team focused on in vitro compound optimization. James received his B.S. in Human Biology from the State University of New York at Albany.

Grover P. Miller

Grover P. Miller is a full Professor in the Department of Biochemistry and Molecular Biology with a joint appointment in Biomedical Informatics at the University of Arkansas for Medical Sciences. He received BS degrees in Biochemistry and Chemistry with minors in English and French from the Louisiana State University. He obtained his PhD in Chemistry mentored by Stephen J. Benkovic at the Pennsylvania State University and subsequent postdoctoral training as an NIH NRSA fellow mentored by F. Peter Guengerich at Vanderbilt University. His research spans experimental and computational approaches to assess metabolic activation and detoxification of drugs, pollutants, and dietary compounds from the perspective of a chemist.

Kaushik Mitra

Kaushik Mitra heads the Molecular and Investigative Toxicology group within the Department of Safety Assessment at Merck. He transitioned to this function in 2016 following a career for 13 years in the Department of Pharmacodynamics, Pharmacokinetics and Drug Metabolism where he held leadership roles in biotransformation and ADME groups. His research interests focus on mechanisms of drug-induced adverse effects such as liver injury and genetic toxicity. Kaushik received his Ph.D. in Organic Chemistry from the University of Missouri, Columbia and subsequent post-doctoral training in Biological Engineering from the Massachusetts Institute of Technology.

Ivonne M. C. M. Rietjens

Ivonne M.C.M. Rietjens is full professor and head of the division of Toxicology at Wageningen University, The Netherlands. She is a member of the Royal Netherlands Academy of Arts and Sciences (KNAW), and chair or vice chair of many national and international advisory committees in the field of risk assessment. Her research focuses on the risk evaluation of food borne natural toxins with an emphasis on the role of reactive intermediates and DNA adduct formation, physiologically based kinetic (PBK) models for bioactivation and detoxification, genetic polymorphisms and consequences of life style factors for individual sensitivity and risk assessment and alternatives for animal testing.

Donglu Zhang

Donglu Zhang is interested in applying drug metabolism studies in drug design and development of both small molecule drugs and antibody-drug conjugates (ADCs). He received the Sir James Black Award for discovery of and original research on Eliquis from British Pharmacological Society (2018) and the Oddetti and Cushman Award for invention of mass defect filtering method (MDF) from Bristol-Myers Squibb (2007). He co-edited two books: Drug Metabolism in Drug Design and Development (2008) and ADME-enabling Technologies in Drug Design and Development (2012). He is on Editorial Board of Drug Metabolism and Disposition and Xenobiotica. He received a Ph.D. in Organic Chemistry from University of Utah and had postdoctoral training at US Food and Drug Administration.