Industries

Aerospace & Defense

EAG is your R&D partner, working with aerospace and defense manufacturers and suppliers to create faster, safer and more reliable aircraft and components. We use the most advanced…

EAG is your R&D partner, working with aerospace and defense manufacturers and suppliers to create faster, safer and more reliable aircraft and components. We use the most advanced analytical methodologies to answer complex engineering, materials and manufacturing problems, from evaluating the purity of new materials to confirming the characteristics of ceramic matrix composites. For research, development and production, we work alongside your technical staff to formulate and troubleshoot the next generation of aerospace and defense materials.

Chemicals & Basic Materials

For over 50 years, EAG’s scientists have applied advanced analytical techniques to solve tough problems and support R&D activities for manufacturers and users of a wide variety…

For over 50 years, EAG’s scientists have applied advanced analytical techniques to solve tough problems and support R&D activities for manufacturers and users of a wide variety of chemicals and materials. EAG offers reliable analytical results, development support for novel products, and answers to complex problems for manufacturers of chemicals used in metals, fibers, plastics, coatings, adhesives, construction materials, textiles, lubricants and more.

Consumer Products

Consumer products manufacturers and partners turn to EAG to answer R&D questions, ensure supply chain quality, respond to regulatory requirements and ensure well-supported legal…

Consumer products manufacturers and partners turn to EAG to answer R&D questions, ensure supply chain quality, respond to regulatory requirements and ensure well-supported legal arguments. EAG scientists have helped all types of consumer products companies accelerate innovation, resolve manufacturing concerns and comply with evolving regulations.

Food & Agriculture

Drive R&D productivity and keep pace with evolving environmental regulations. From agrochemical development to evaluating innovative packaging solutions, EAG scientists support…

Drive R&D productivity and keep pace with evolving environmental regulations.

From agrochemical development to evaluating innovative packaging solutions, EAG scientists support the agriculture/food s industry with scientific expertise required to enhance shelf life, ensure product safety and understand environmental impact. Whether in need of food quality investigations or help supporting regulatory filing of new chemicals, ask EAG. WE KNOW HOW.

Law

When a business’s brand and reputation is at stake, clients turn to EAG’s litigation support services for dependable scientific answers. Since 1959, our scientific expertise,…

When a business’s brand and reputation is at stake, clients turn to EAG’s litigation support services for dependable scientific answers. Since 1959, our scientific expertise, testing and testimony have supported legal strategies for intellectual property, product liability and insurance cases. Our scientists offer expertise in technology, life sciences, electronics, industrial and consumer products, having tested a broad array of materials for legal challenges. We understand the unique needs of legal projects – speed, effective communication, reliability and confidentiality.

Medical Device & Diagnostics

From initial concept and prototypes to verification/validation, submission and launch, EAG Laboratories is your partner in medical device development. From implant…

From initial concept and prototypes to verification/validation, submission and launch, EAG Laboratories is your partner in medical device development. From implant biocompatibility studies to surface chemistry for contact lenses, we have the experience and techniques to characterize, test and assure purity of medical devices and their materials, components, products and packaging. By utilizing our unique expertise in materials sciences, chemistry, electronics and regulatory support, EAG empowers device companies to create new ways to heal and improve patient quality of life.

Pharmaceuticals

Overcome R&D roadblocks with technical and regulatory know-how. For over two decades, EAG scientists have helped solve complex issues for the pharmaceutical Industry. Using…

Overcome R&D roadblocks with technical and regulatory know-how. For over two decades, EAG scientists have helped solve complex issues for the pharmaceutical Industry. Using multidisciplinary science and engineering, we help improve product development efficiency, avoid regulatory setbacks and uncover sources of problematic manufacturing issues. From GLP and cGMP studies to contaminant and packaging investigations, the scientists of EAG support every phase of the product lifecycle.

Technology

For the high-tech industry, EAG is the leader in materials characterization, surface analysis, microscopy and electronics testing. Our scientists and engineers troubleshoot and…

For the high-tech industry, EAG is the leader in materials characterization, surface analysis, microscopy and electronics testing. Our scientists and engineers troubleshoot and solve issues with consumer electronics, chip packages, printed circuit boards, displays, sensors, high-speed communications and more. We meet the demanding needs of technology innovation, enabling our clients to have confidence in their research & development, supply chains, and ultimately their manufacturing processes

Services

Pharmaceutical & Biopharmaceutical Development Services

EAG Laboratories’ pharmaceutical development services group is now part of Eurofins Biopharma Product Testing. Eurofins BioPharma Product Testing offers…

EAG Laboratories’ pharmaceutical development services group is now part of Eurofins Biopharma Product Testing.

Eurofins BioPharma Product Testing offers unprecedented, multi-location capacity and unmatched expertise through the largest harmonized network of bio/pharma product testing laboratories worldwide. From performing IND-enabling studies to full CMC analytical and QC support, we join your R&D team as a true partner, providing expert guidance to balance regulatory expectations with expediency and cost, and approach technical challenges with flexibility and resolve.

Materials Testing & Analysis

When it comes to understanding the physical structure, chemical properties and composition of materials, no scientific services company offers the breadth of experience, diversity…

When it comes to understanding the physical structure, chemical properties and composition of materials, no scientific services company offers the breadth of experience, diversity of analytical techniques or technical ingenuity of EAG. From polymers to composites, thin films to superalloys—we know how to leverage materials sciences to gain a competitive edge. At EAG, we don’t just perform testing, we drive commercial success—through thoughtfully designed investigations, technically superior analyses and expert interpretation of data.

Environmental Testing & Regulatory Compliance

Having helped develop the test methods that shape current regulatory guidelines, EAG chemists, biologists and toxicologists have evaluated the environmental impact of thousands of…

Having helped develop the test methods that shape current regulatory guidelines, EAG chemists, biologists and toxicologists have evaluated the environmental impact of thousands of active ingredients and formulations—from pesticides and pharmaceuticals to industrial chemicals and consumer products. Whether you are exploring “what if” scenarios, registering a new active ingredient or formulation, responding to a data call-in or seeking to understand the latest guidance, turn to EAG for technical excellence, sound advice, GLP-compliant study execution and expert interpretation.

Microelectronics Test & Engineering

Whether connecting the internet of things, guiding surgical lasers or powering the latest smart phone, integrated circuits and microelectronics touch nearly every aspect of human…

Whether connecting the internet of things, guiding surgical lasers or powering the latest smart phone, integrated circuits and microelectronics touch nearly every aspect of human life. In the world of technology, innovation and continuous improvement are imperatives—and being able to quickly and reliably test, debug, diagnose failures and take corrective action can make the difference between a doomed product launch and building a successful global brand. EAG offers you the world’s largest and most diverse collection of specialized analytical instrumentation, capacity to perform a variety of microelectronic tests in parallel, and the multi-disciplinary expertise required to draw true insight from data.

Custom Synthesis & Radiolabeling

No contract service provider has more experience performing custom synthesis and producing isotopically labeled compounds to support product development in life science, chemical…

No contract service provider has more experience performing custom synthesis and producing isotopically labeled compounds to support product development in life science, chemical and related industries than we do. From 14C and 3H radiolabeled clinical trial materials synthesized under cGMP, to stable-labeled active ingredients for metabolism and environmental fate/effects testing, turn to EAG. We have extensive experience with multi-step and other complex synthesis projects, and our comprehensive, in-house analytical services ensure quick turnaround of purity and structural confirmation.

Crop Biotechnology & Development

EAG combines biotechnology and protein characterization expertise with more than 50 years' experience analyzing chemical compounds in plant and environmental matrices to address…

EAG combines biotechnology and protein characterization expertise with more than 50 years’ experience analyzing chemical compounds in plant and environmental matrices to address the growing needs of the biotechnology crop industry. We offer a wide range of techniques required to fully characterize the event insertion and expressed proteins, as well as the various studies required to confirm the food, feed and environmental safety of products that represent the trait. From early-stage protein confirmation to GLP-compliant EDSP and allergenicity testing, we help you make faster, more informed development decisions and comply with evolving global regulations of genetically engineered crops.

Litigation Support & Expert Testimony

When you need solid science and investigative engineering to address product failures, inform legal strategy, protect intellectual property or address product liability disputes,…

When you need solid science and investigative engineering to address product failures, inform legal strategy, protect intellectual property or address product liability disputes, turn to EAG. We’ve provided technical consulting, analysis and expert testimony for hundreds of cases involving the aerospace, transportation, medical device, electronics, industrial and consumer product industries. Our team of experts understands the legal process and your need for responsiveness, effective communication, scientifically defensible opinion and confidentiality. From professional consulting to data review to trial preparation and expert witness testimony, ask EAG.

Techniques

Chromatography

Using an array of advanced separation techniques and innovative technology, we conduct highly precise analytical chromatography for various industries. Whether you want a closer…

Using an array of advanced separation techniques and innovative technology, we conduct highly precise analytical chromatography for various industries. Whether you want a closer look at the purity of your pharmaceutical or need to better understand an agrochemical’s components, EAG has the expertise to separate and evaluate any compound.

Mass Spectrometry

Need to evaluate the molecular structure of a compound or identify its origins? EAG knows how. With state-of-the-art tools, we can separate, vaporize and ionize the atoms and…

Need to evaluate the molecular structure of a compound or identify its origins? EAG knows how. With state-of-the-art tools, we can separate, vaporize and ionize the atoms and molecules in almost any pure or complex material to detect and obtain mass spectra of the components. We rely on decades of experience in mass spectrometry to provide our clients with precise analyses and the best detection limits.

Imaging

EAG is a world leader in high-resolution imaging down to the atomic level. We offer unmatched analytical know-how, generating extremely detailed surface and near surface images…

EAG is a world leader in high-resolution imaging down to the atomic level. We offer unmatched analytical know-how, generating extremely detailed surface and near surface images for various industries, from consumer electronics to nanotechnology. Using state-of-the-art equipment and innovative techniques, we conduct expert imaging to aid in failure analysis, dimensional analysis, process characterization, particle identification and more. If you want to investigate a material with angstrom scale resolution, you can count on EAG to get the job done quickly and precisely.

Spectroscopy

EAG offers a vast array of spectroscopic techniques to clients in various industries, from defense contractors to technology pioneers. We combine unparalleled expertise and…

EAG offers a vast array of spectroscopic techniques to clients in various industries, from defense contractors to technology pioneers. We combine unparalleled expertise and methodology with cutting-edge technology to analyze your organic, inorganic, metallic and composite materials for identification, compositional, structural and contaminant information. Whether you need expert spectroscopic analysis to improve your production process or to surmount a technical challenge, EAG is up to the task.

Physical/Chemical Characterization

Need to identify your unique material? Want to analyze the thermal properties of a sample, or measure the success of a process step? If it has to be done quickly and it has to be…

Need to identify your unique material? Want to analyze the thermal properties of a sample, or measure the success of a process step? If it has to be done quickly and it has to be done right, you can count on EAG. We offer a range of adaptable techniques and innovative methods to evaluate the physical and chemical characteristics of any compound. Our highly precise testing and analytical services will improve your production process, expedite R&D and help you conquer any technical challenge.

About

A Global Scientific Services Company

One of the most respected names in contract research and testing, EAG Laboratories is a global scientific services company operating at the intersection of science, technology and…

One of the most respected names in contract research and testing, EAG Laboratories is a global scientific services company operating at the intersection of science, technology and business. The scientists and engineers of EAG apply multi-disciplinary expertise, advanced analytical techniques and “we know how” resolve to answer complex questions that drive commerce around the world.

Our Customers

Science and technology transcend industry boundaries, and so does demand for EAG’s expertise. We partner with companies across a broad spectrum of high-tech, high-impact and…

Science and technology transcend industry boundaries, and so does demand for EAG’s expertise. We partner with companies across a broad spectrum of high-tech, high-impact and highly regulated industries. We help our customers innovate new and improved products, investigate manufacturing problems, perform advanced analyses to determine safety, efficacy and regulatory compliance, and protect their brands.

Our Company Culture

EAG’s corporate culture is firmly rooted in four guiding principles: “foster a growth mindset,” “find a better way,” “earn more loyal customers,” and “win…

EAG’s corporate culture is firmly rooted in four guiding principles: “foster a growth mindset,” “find a better way,” “earn more loyal customers,” and “win together.” Across all of our 20+ locations, you will find a true passion for science and the power of science to improve the world we live in. Hear what some of our ~1200 scientists, engineers and support personnel say about what it means to be part of EAG Laboratories.

Careers

EAG is growing, and we are always looking for talented, problem-solving oriented individuals to join our company. If you have a “we know how” spirit, we want to hear from you.…

EAG is growing, and we are always looking for talented, problem-solving oriented individuals to join our company. If you have a “we know how” spirit, we want to hear from you. Browse current openings now, and re-visit our careers page often.

How do you make better development decisions faster?

The Importance of Stereo-Selective Metabolism in Drug Discovery and Development

WHITE PAPER

By James Schmidt, EAG Life Sciences Senior Scientific Advisor, for Trace Analysis and Structural Chemistry, Custom Synthesis, and Product Chemistry

INTRODUCTION

“In order to understand the actions of drugs it is an absolute necessity to have knowledge of the transformations they undergo in the body…we must not judge drugs according to the form and amount administered, but rather according to the form and amount which actually is eliciting the action.”1

This statement was written more than 150 years ago – in 1859 – by Rudolph Buchheim (1820–79), a pioneer in experimental pharmacology. It lays out as elegantly as any modern statement or regulatory guidance the very mission and importance of drug metabolism, pharmacokinetics (“amount”), and pharmacology (“action”), and – especially – the role of metabolite profiling and identification (“transformations” and “form”).

There are few aspects of drug metabolism and metabolite profiling more essential – and more interesting – than exploring stereo-selective (also known as enantio-selective or chiral-selective) metabolism. For the better part of a century, the consideration of chirality in drug metabolism was limited to academic study and/or to natural products, owing in no small part to the limits of separations chemistry. However, chirality has been earning ever-greater importance in drug discovery and development, such that most of the new molecular entities reaching the market in the first decades of the 21st century are single enantiomers, rather than the racemic mixtures (or achiral drugs) that dominated the latter half of the 20th century. Stereo-selective metabolism has important impacts on scientific aspects such as pharmacokinetics, pharmacodynamics, drug safety, and bio-analytical chemistry; but also on regulatory, intellectual property, business and product development, and other important considerations. 2-4

TYPICAL REACTIONS

While direct enantio-selective effects on the physical–chemical aspects of adsorption, distribution, or elimination are minimal or are only now being studied, their effects on metabolism are the rule rather than the exception. This applies to the drugs as substrates or products and applies across multiple enzyme systems (P450, Phase II, etc.). Examples include:

The prochiral/achiral metabolism (carbonyl reduction) of haloperidol (in humans, S-hydroxy-haloperidol is preferred) to a chiral product

The prochiral/achiral metabolism (carbonyl reduction) of haloperidol (in humans, S-hydroxy-haloperidol is preferred) to a chiral product (above);

  • The chiral to chiral transformation of (S)-warfarin to (S)-7- or (S)-6-hydroxywarfarin;
  • Chiral to achiral transformations, such as those involving 1,4-dihydropyridine calcium antagonists to their pyridine analogs;
  • Chiral to diastereomer transformations such as the keto-reduction of warfarin, resulting in two pairs of diastereomeric alcohols (below);

Chiral to diastereomer transformations such as the keto-reduction of warfarin, resulting in two pairs of diastereomeric alcohols

  • Chiral inversions (enzymatic and non-enzymatic) such as those that occur with 2-arylpropionic acid NSAIDS.

POTENTIAL DRUG-DRUG INTERACTIONS

The administration of racemic drugs is polypharmacy, by definition; add in yet another drug, and the effects on drug-drug interactions (DDIs), pharmacology, or other drug safety considerations can be significant when the induction or inhibition of one drug influences the PK behavior of the other(s), and reinforces the importance of considering the exploration of chirality in metabolite profiling exercises.

Examples include the interaction of warfarin with cimetidine [decreases the clearance of (R)-warfarin] or with sulfinpyrazone [decreases the clearance of (S)-warfarin]. Likewise, racemic mixtures can exert effects on pharmacodynamics and/or safety:

  • The efficacy may be in a single enantiomer, the antipode being biologically inert;
  • The pharmacological activity of each of the enantiomers may be different, such that each can be developed on its own merits;
  • The enantiomers may have opposite effects at the same target;
  • The pharmacological activity lies in both enantiomers, but adverse safety is only associated with one.

BIO-ANALYTICAL CHEMISTRY APPROACHES

As mentioned earlier, a driving factor in the increased appreciation of chiral-driven drug metabolism, PK, and pharmacodynamics has been an improvement in column chemistries to achieve the necessary separations. Indeed, it has been stated that the “development of complex PK models and plasma–concentration–effect relationships based on ‘total’ drug concentrations following administration of a racemate are of limited value and potentially useless.” 5

The preferred method is direct separation on a chiral stationary phase (e.g., polysaccharide or immobilized protein). An alternative is an indirect method in which the enantiomers are derivatized with a chiral reagent to produce diastereoisomers, which can then often be separated on conventional column chemistries.

Bio-Analytical Chemistry Approaches6

As with all quantitative analytical chemistry, the methods should aim for accuracy and reproducibility, with minimal sample preparation, and the employment of sample-friendly mobile phases or pH. However, special diligence in method development and validation is required for chiral separations. The preferred method is direct separation on a chiral stationary phase (e.g., polysaccharide or immobilized protein). An alternative is an indirect method in which the enantiomers are derivatized with a chiral reagent to produce diastereoisomers, which can then often be separated on conventional column chemistries.

AN EXAMPLE OF STEREO-SELECTIVE METABOLISM

The current movement towards single enantiomers as drug candidates, noted above, should result in mitigation of the DDIs that are potentially associated with racemic mixtures. This does not alleviate the concern or challenges that are associated with achiral-to-chiral transformations and/or chiral-to-chiral or chiral-to-diastereomer transformations.

A hypothetical case study (based on actual data, but anonymized) of stereo-selective metabolism and metabolite profiling, is described below. 7,8

Consider a small molecule drug candidate that demonstrates good efficacy in a mouse pharmacology model and exhibits acceptable safety and PK profiles in preclinical studies. Early metabolite profiling efforts in mouse indicated that the most significant metabolite pathway was keto-reduction to form the corresponding alcohol (similar to the example of haloperidol described above), now with a chiral center:

Early metabolite profiling efforts in mouse indicated that the most significant metabolite pathway was keto-reduction to form the corresponding alcohol, now with a chiral center:

Based on these findings, attention should be given to possible stereo-selective metabolism to the chiral alcohol, with several important questions to consider:

  • What is the in vitro metabolism of the compound in other preclinical species and in human?
  • Can an initial bio-analytical method of the enantiomers be achieved with minimal method development/sample prep?
  • Can the bio-analytical method be optimized and made suitable for validation?
  • Is there stereo-selective (i.e., to the R- or S-form) metabolism to the alcohol?
  • Do the in vivo results reflect the in vitro results?
  • What enzyme is responsible for the metabolism?
  • Are there regulatory/clinical/intellectual property/business development implications?

In vitro experiments (liver S9) in multiple species indicated that metabolism to the S-enantiomer of the keto-reduced metabolite was preferred (>90% in rat, dog, and human; >80% in mouse). However, the keto-reduced alcohol was not observed in monkeys: this would have significant implications for selection of species for toxicological studies. Pharmacokinetic experiments in mouse, rat, and dog were all consistent with the companion in vitro experiments: that is, the S-enantiomer was preferred over the R-enantiomer, and consistent with the ratios observed in the in vitro experiments. Furthermore, plasma exposure of the keto-reduced metabolite in other species was several-fold higher than the parent compound (which, in turn, raises the typical questions for a “disproportionate metabolite”). Finally, the S-enantiomer of the keto-reduced metabolite was also found to have significant efficacy against the target.

From a bio-analytical perspective, initial analyses employed an immobilized protein column at hand that offered very good separation of the enantiomers of the keto-reduced metabolite, but required long (>60 minutes) run times, yielded suboptimal peak shapes (and corresponding suboptimal sensitivity), and was not robust enough to accommodate repeated injections of biological samples. Subsequent investigations resulted in the successful employment of a different chiral column chemistry that allowed for shorter run times and improved sensitivity so that the metabolite could be monitored in clinical studies in a cost-effective manner.

This hypothetical case study provides a good example of the need to consider possible enantio-selective metabolism and its impact on PK, pharmacodynamics, toxicology, and bio-analytical chemistry; not to mention regulatory, intellectual property, business and product development, and other important considerations. 8

STEREO-SELECTIVE METABOLISM AT EAG LABORATORIES: WE KNOW HOW

EAG has more than three decades of experience in the conduct of ADME (adsorption, distribution, metabolism, and excretion) studies with preclinical species to support drug discovery and development.

Our study directors design and oversee the in-life stages at partner sites with AAALAC-accredited facilities that are vetted and qualified by EAG. Dose preparation, mass balance determinations, sample preparation, extractions, metabolite profiling, and unknown metabolite identification are performed by highly experienced scientists in EAG’s metabolism groups. Our scientists can also facilitate related services such as quantitative whole body autoradiography.

Specific capabilities include:

  • Experts with significant publication records in drug metabolism – We Know How
  • Radiolabeled and non-radiolabeled ADME studies –preclinical species or human clinical trial support
  • Sample preparation and extraction method development
  • Chromatographic method development
  • Radiochromatographic profiling
  • LC-MS/MS identification (including high resolution mass spectrometry)
  • Proposal of metabolic pathways
  • Radio-labeled, stable-labeled or non-radiolabeled synthesis of drug and metabolites

ABOUT THE AUTHOR

James Schmidt, EAG Life Sciences Senior Scientific Advisor for Trace Analysis and Structural Chemistry, Custom Synthesis, and Product Chemistry, brings more than three decades of experience in xenobiotic metabolism, bio-analytical chemistry, and structural elucidation with private, government, and industrial laboratories. His special interests include small molecule metabolic stability, metabolite profiling and identification, chiral separations, and pharmacologically active metabolites. He is the author or co-author of several peer-reviewed posters and papers, as well as scientific reports to satisfy regulatory requirements of both the EPA and FDA. Most recently, he contributed the chapter on “Metabolite Profiling” to the book New Horizons in Predictive Drug Metabolism and Pharmacokinetics (Alan G. E Wilson, ed., RSC Publishing, 2015). James is based at our Columbia, Missouri (formerly ABC Laboratories) location.

REFERENCES

  1. A. Conti and M. H. Bickel, Drug Metab. Rev., 1977, 6, 1–50.
  2. V. Campo, L. Bernardes and I. Carvalho, Curr. Drug Metab., 2009, 10, 188–205.
  3. D . Brocks, Biopharm. Drug Dispos., 2006, 27, 387–406.
  4. Chirality in Drug Design and Development, ed. I. Reddy and R. Mehvar, CRC Press, New York, 2004.
  5. A . Hutt, Metab. Drug Interact., 2007, 22, 79–112.
  6. Adapted from Campo, et al. (ref. 2, above)

 

Hypothetical Case Study: The author has had the privilege of working on several interesting examples of stereo-selective metabolism in his career. The hypothetical case study presented in this white paper is based on one of those examples; additional data on the example is reported here:

  1. J. Schmidt, A. Nouraldeen, L. Moran, L. Li and A. Wilson, Enantio-selective and Species-Dependent Carbonyl Reductase Metabolism of LX6171, 12th Annual Conference on Drug Metabolism and Applied Pharmacokinetics, 2009.
  2. L. Li, W. Heydorn, J. Kramer, A. Nouraldeen, J. Schmidt, J. Jiang, L. Moran and A. Wilson, Metabolism Mediated CYP2B Induction by LX6171 (3′-chlorobiphenyl-4-yl)-1-(pyrimidine-2-yl) piperidin-4-yl methanone in the Rat, International Society for the Study of Xenobiotics (ISSX) Annual Meeting, 2009.

 

Other recent case studies are reported here:

  1. J. Schmidt, “Metabolite Profiling,” in A.G.E. Wilson (ed.), New Horizons in Predictive Drug Metabolism and Pharmacokinetics, RSC Publishing, Cambridge, UK, 2015.

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