Discussion and Conclusion

The Parkinson's-Reversing Breakthrough

Treatment Options for Parkinson Disease

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Progress in optimizing the way to carry out in vitro metabolic studies in R&D has been constant over the last decade. In a way, xenobiotic metabolism represents a quite unique domain within R&D. It is effectively one of the sole disciplines present at every major step in R&D, and provides pivotal information to pharmacologists, chemists, toxicologists, and clinical scientists. It has therefore evolved toward the use of a large range of metabolic tools, allowing the rapid understanding of a drug's fate.

This nonexhaustive panel of in vitro tools has been very much used by pharmaceutical companies to better select drug candidates in high-throughput screening (HTS) programs. However, go/no-go decisions on simple parameters are somewhere an idealistic search for the (perfect) drug. The actual strategies have moved toward better evaluation, anticipation, and control of the potential safety and efficacy issues that one can, and probably will, encounter at a certain degree when administering a xenobiotic to a living organism.

These safety and efficacy aspects have been discussed in this chapter, trying to show how in vitro metabolism tools can better address, at very early stages, the nature and the importance of metabolites formed throughout species as well as the drug interactions risks.

These two issues have been recognized by regulatory authorities as major and the studies to be undertaken have been defined quite precisely for development programs and registration purposes in recent draft guidelines on safety testing of metabolites and predictions of drug interactions. These new requirements will have to be discussed and integrated by research teams. But one has to keep in mind that getting a similar level of understanding in research projects on series of drugs will only be possible if one can further adapt the tools using new technologies and apply different and more global interpretation strategies.

Screening programs have in a way broken down the important mechanisms involved in drug disposition (absorption, metabolism, etc.), trying to avoid their potential negative consequences in humans (variability, drug interactions, etc.). Today a large number of individual key parameters (solubility, permeability, rates of metabolism, inhibition and induction characteristics, etc.) or even surrogate markers (log P parallel artificial membrane permeability assay (PAMPA), etc.) of these parameters exist to screen series of compounds.

Despite the large number of tests used routinely, a number of weak points remain to be addressed. Because these programs have been successful in selecting more stable compounds as regards CYP oxidative pathways, the role of non-CYPs has become more apparent and represents one important aspect to be developed by metabolism scientists.

Nonspecific binding to microsomes will have to be further integrated on a systematic basis in these early programs. The incubation of microsomes, in the presence of plasma or otherwise, should enable these binding issues to be simply addressed in routine tests.

The impact of gastrointestinal tract enzymes (endogenous enzymes from small intestine but also exogenous microflora enzymes from colon) on drug metabolism as well as on the risk of drug interaction is another aspect that has been neglected in early evaluations. In this respect, there are no real validated human tools as regards in vivo extrapolations. The CYP activity profile of human gut microsomes, in the presence of protease inhibitors, is variable with the time of storage with sometimes a dramatic loss in certain activities, hence a limited predictivity.

On the other hand the in vivo relevance of well-known human liver tools such as microsomes and hepatocytes is regularly questioned. The former, even though they are used as pools of several livers, are frequently not representative of the average population because these pools are difficult to constitute. An alternative, discussed in this chapter, would be to reconstruct human microsomes using expressed enzymes. This is a way to standardize microsomes, better representing the average population for all major and minor enzymes, or if needed any other type of subpopulation, i.e., integrating the polymorphic aspects of these enzymes. Hepatocytes, mainly because of their poor availability, are not really adapted to large screening programs. Cell lines as well as stem cells or medullar cells are probably going to resolve these aspects in the near future.

The domain having recently progressed the most in metabolism screening is probably the evaluation of the induction potential. Nuclear receptor activation assays, even though the exact correlation with the in vivo induction profile still has to be fully validated, are useful for evaluating the induction potential within series of compounds. Human hepatocytes, as a reference model for induction studies, can be used on smaller series of compounds at a somewhat later stage.

As regards the nature of metabolites, the identification of major metabolic pathways in drug discovery programs has always represented a significant analytical challenge. It seems that with the new technological advances, this information, very frequently asked for by chemists, pharmacologists, and toxicologists in research groups, will be available on small series of compounds. It will contribute to more precisely determine their positive (efficacy) and negative (safety) importance in nonclinical and clinical programs.

However, the future challenge is more in combining this early information, and thus reconstructing partially or totally these mechanisms at the level of the cell, the organ, or the organism.

At the cellular level coculture or coincubation systems (hepatocytes and plasma or microsomes and plasma) better integrate the different equilibrium occurring in and between the cells. Measuring individual parameters such as protein binding on one side and clearance of the drug on the other side and mathematically combining them to predict the bioavailability has proven to fail in a number of cases.

At the organ or the organism level, the use of physiologically-based pharmacokinetics (PBPK) models is a way to extrapolate in vitro data in order to get in vivo time concentration profiles. This approach allows one to challenge the multiple assumptions made when measuring in vitro parameters and extrapolating them to the entire organism (see 5.37 Physiologically-Based Models to Predict Human Pharmacokinetic Parameters).

On the other hand, the enormous amount of absorption, distribution, metabolism, and excretion (ADME) data generated over the last decade in HTS programs has been used to develop in silico prediction packages. Even though these in silico approaches need further refinements and validations, they will be of great value when linked to PBPK models and will probably in the future replace entire parts of HTS programs.

For drug interaction predictions, based on the inhibition and induction potential as well as knowledge of the enzyme(s) involved in the drug's metabolism, one can get a clear picture of the potential risks of coadministered drugs in the clinic, using drug interaction databases such as AurQuest,66 DIDB,99 drug interaction,100 or Gentest websites.101 Even though interlaboratory differences in kinetic parameters (Km, Vmax, CLint, Ki, and IC50) can be quite large in the literature, it is a useful source of in vitro data, especially with packages such as AurQuest integrating the calculation of drug interaction risks.

In conclusion, in vitro metabolism tools have been recognized by the recent guidelines on drug interactions as valid decision-making tools able to avoid unnecessary in vivo studies. In parallel, more information on the identity and the concentration of metabolites will potentially be available helping for a better interpretation of drug safety and efficacy programs. After almost a decade of selection of drug candidates on simple ADME parameters, the need for more global tools allowing to better combine this early information has emerged. New approaches, such as physiological models, integrating in vitro parameters, and emerging molecular modeling tools will, without doubt, be key elements in the future selection processes of drug candidates. They represent also valuable tools to optimize future clinical studies (see 5.34 Molecular Modeling and Quantitative Structure-Activity Relationship of Substrates and Inhibitors of Drug Metabolism Enzymes).

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Biographies

Yannick Parmentier studied Pharmacy in Lille (Faculté des Sciences Pharmaceutiques et Biologiques - France) and molecular and cellular pharmacology in 'Ecole Normale Supérieure' of Paris VI.

He spent 1 year in the Institut de Recherches Servier at Croissy (France) to study the involvement of PPARg nuclear receptors in the cellular differentiation of adipocytes.

In 1998, he worked 18 months in the Metabolism Department at Servier Research and Development (England) as research officer. He was in charge of the validation of the cytochrome P450 co-expressed functionally in E. coli with human NADPH-P450 reductase and engineered by Dundee University (Scotland).

He took on a position as Study Director in the Metabolism Department at Servier (France) in 1999 before being appointed as Section leader in the DMPK predevelopment Division in 2005 in charge of the supervision of all ADME predevelopment selection programs as well as the development of new in vitro models.

Marie-Jeanne Bossant studied Analytical Chemistry, Metabolism and Pharmacokinetics in Paris (Faculté des Sciences Pharmaceutiques Paris XI - France) and obtained his PhD on PAF-Acether: characterization and quantitation (collaboration between Paris XI and INSERM U200, Clamart - France - J Benveniste)

She spent 2 years as a postdoctoral fellow at the NIH (NIAAA Bethesda - USA - Norman Salem Jr - 1989-91) period during which, she was involved on metabolism of lipids in alcoholic patients, before taking up a position as Study Director in the Metabolism Department at Servier (France) in 1991.

She has since been involved in medical writing for registration purposes, design of metabolism databases and is currently following the predevelopment of New Chemical Entities for both their Pharmacokinetic and Metabolic properties.

Marc Bertrand studied Biology and Physiology in Clermont Ferrand (University of Clermont Ferrand - France) and then Biochemistry in Lyon (University Claude Bernard - Lyon - France) and obtained his PhD in 1987 at INSERM U171 (Lyon - Pr J-F Pujol) on central catecholaminergic systems developing an in vitro brain slice model.

He took up a position as Study Director in the Metabolism Department at Servier (Orléans - France) in June 1987, an important part of his role being to develop and implement in vitro models.

In 1991, he was appointed Head of the Metabolism Department (Orleans - France) managing both in vitro experiments such as interspecies comparisons, drug-drug interaction and in vitro based pharmacokinetic parameter predictions as well as in vivo animal and human metabolism studies for registration purposes.

From 1998 onward he took over the Drug Discovery Support Department, responsible for the generation and integration of biopharmaceutical parameters (physicochemical, metabolism, pharmacokinetics, and safety fields ) within research programs as well as the development of new approaches in early discovery support (new in vitro based models, transcriptomics and in silico molecular modeling prediction tools).

Bernard Walther studied Pharmacology in Nancy (Faculté des Sciences Pharmaceutiques et Biologiques - France) and obtained his PhD at the Centre du Medicament (Nancy - Pr G Siest) on cytochrome P450: characterization and role in the brain.

He spent 3 years as a postdoctoral fellow at the School of Pharmacy, University of Lausanne (Switzerland - Pr B Testa - 1986-88) period during which, he was involved on QSAR and CNS uptake projects. He was also supervising a PhD on the hepatic and cerebral hydrolysis of nicotinic acid esters and the relation between structure and metabolism, before taking up a position as Study Director in the Metabolism Department at Servier (France) in 1988.

In 1991, he was appointed as General Manager of the Pharmacokinetic and Metabolism laboratory at Servier Research and Development (England).

From 1995 onward he took over the Pharmacokinetic and Metabolism Centre as Director of the Pharmacokinetics Centre at Technologie Servier in France (Orleans), involved in drug screening and development and more recently dedicated to early discovery and predevelopment programs as well as the implementation of new technologies.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 5) 0-08-044518-7; pp. 231-257

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