SCIENCE & TECHNOLOGY
TROUBLESOME DRUG METABOLITES ACS MEETING NEWS: Toxicologists pool their knowledge
to advance safety testing of drug candidates STEPHEN K. RITTER, C&EN WASHINGTON
DRUG DEVELOPMENT is perhaps the
Guengerich emphasized. “This problem has prompted an increased interest in human-specific drug metabolites and their potential toxicity,” he said. In an effort to help inform the research community, Guengerich, an associate editor of ACS’s Chemical Research in Toxicology, coordinated a special issue of the journal published this past February on human metabolites in safety testing. As a follow-up to reach a broader audience and provide a forum for discussion, Guengerich and Nicholas A. Meanwell of Bristol-Myers Squibb organized the ACS symposium.
noted. “But for the purpose of drug safety most complicated of all human endeavors. testing, the key interest is looking at the After exhaustive research to discover a differences in metabolism between hudrug candidate for a target ailment, pharmans and animals.” THE ISSUE of human metabolites in maceutical scientists must confirm the For example, although rat and human drug testing has been debated by FDA and efficacy of the compound and determine if P450 1A1 have the same name, they are not pharmaceutical companies for several it’s toxic to people. As part of this process, the exact same enzyme, Guengerich said. years, noted symposium speaker Aisar H. researchers have to take a step back and They are about 80% identical, he noted, Atrakchi of FDA’s Center for Drug Evalualook at any possible mischievous by-proddiffering by about 100 amino acid residues, tion & Research. A slowly formed consenucts created when the drug circulates in so it’s not surprising that they are going to sus led FDA to issue a guidance document the body and is metabolized. Any hints of vary in how they interact with drugs and on safety testing of small-molecule drug toxicity stemming from major metabolites produce drug metabolites. Similar differmetabolites in early-stage drug developcould derail the prospective drug and ruin ences occur for conjugating and hydrolysis ment in February 2008, Atrakchi said. She its chances of reaching blockbuster status. enzymes, he said. provided a bit of the history and explained How the Food & Drug Administration Overall, it is extremely difficult to FDA’s rationale and expectations for toxicviews these problematic human drug make extrapolations between animals and ity testing of metabolites during her talk. metabolites and the hoops that pharmapeople in safety testing for metabolites, The FDA guidance states that any huceutical companies must jump man drug metabolite formed at through to identify and work greater than 10% concentration OCH3 around them were the topics of of the parent drug compound O discussion during a symposium circulating in the blood is NH2 OCH3 held earlier this month at the subject to separate safety testHO HN N N ACS national meeting in Washing, Atrakchi said. In addition, OCH3 ington, D.C., cosponsored by the metabolites that either can’t N N N Divisions of Chemical Toxicolbe detected in animals or are ogy and Medicinal Chemistry. present at much higher levels N M-22OH The liver is the primary in people than in animals are No toxicity OT-7100 Rat organ responsible for drug subject to testing. P450 1A2 metabolism, and most drugs Other triggers that could are substrates for the liver’s lead to additional testing for cytochrome P450 oxidase enmetabolites include drug bindNH2 zymes, explained P450 expert ing to nontarget receptors and Peptide NH2 F. Peter Guengerich, director of compound “structure alerts,” S N Human N Vanderbilt University School of Atrakchi noted. In the latter P450 1A2 N N Medicine’s Center in Molecular case, medicinal chemists know N Toxicology and a symposium that certain types of functional OH N coorganizer. Humans and groups, such as hydrazines, M-23OH adduct mammals used in drug testing thiophenes, anilines, quinones, Human liver toxicity have 50–100 genes that code and nitroaromatics, can be DIVERGING PATHS The experimental analgesic drug for P450s, Guengerich said. troublemakers and lead to toxic OT-7100 is metabolized by the human P450 1A2 enzyme to Between the different species metabolites, she said. Chemists form M-23OH, which conjugates with a peptide to form an the same enzymes often yield try to avoid these groups when adduct that has liver toxicity. In rats, the same enzyme forms similar drug metabolites. But designing drugs, but when they some M-23OH but leads predominantly to M-22OH, which sometimes they don’t. are present they alert chemists shows no toxicity (Chem. Res. Toxicol. 2009, 22, 323). These “Within the human populato be on the lookout for posmetabolic differences highlight some of the perils of testing tion there are P450 variants that sible toxic metabolites and to drug candidates for metabolite toxicity. give rise to some differences in make structural adjustments if drug metabolism,” Guengerich needed. WWW.CEN-ONLINE.ORG
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Although the guidance might not sound too burdensome, it adds more complexity to the already complex drug development process by increasing the number of compounds to evaluate and increasing the expense of an already expensive process. But one point Atrakchi reiterated is that the issued document is a set of recommendations, not a regulatory rule. “The guidance was framed with the best interests of pharmaceutical companies in mind to help them weed out problematic drug candidates early on before the formal New Drug Application is filed,” she said. IN ADDITION to Atrakchi’s presentation,
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three pharmaceutical scientists discussed new ideas and research tools aimed at facilitating metabolite toxicity studies. Abdul Mutlib of Wyeth Pharmaceuticals described how advanced nuclear magnetic resonance spectroscopy techniques can be used to obtain quantitative data on metabolites in blood. This approach can potentially avoid the need to separately synthesize the metabolites for animal testing, he said, which can save time and money, especially on radioisotope-labeled compounds commonly used for in vivo metabolite studies. Pfizer’s R. Scott Obach provided an overview of toxicity mechanisms and presented a study of 24 drugs that have been withdrawn from the market. Obach noted that 14 of the drugs had toxicity associated with metabolites. These metabolites were not human-specific, he pointed out, meaning that additional testing would not have turned up any data that would have raised a red flag and prevented drug approvals. This latter analysis is helpful in sorting out different causes for toxicity, he said, but highlights that metabolite toxicity testing is a tricky business. Merck & Co.’s Clay B. Frederick presented results on the use of ultraperformance liquid chromatography/ high-resolution mass spectrometry that are useful for making drug metabolite profile comparisons between people and test animals. He also noted efforts to create “humanized” mice in which human genes that code for P450 enzymes are inserted into mice, providing better mouse models of human drug metabolism. As the symposium concluded, Guengerich summarized the topic of metabolite safety testing this way: “The issue of human-specific metabolites is a complex one, and much remains to be learned.” ■
