ADME/PK as part of a rational approach to drug discovery

Eddershaw, Peter; Beresford, Alan; Bayliss, Martin K.

doi:10.1016/s1359-6446(00)01540-3

Cited by 213 publications

(107 citation statements)

References 23 publications

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“…Screening strategies early in lead optimization now typically incorporate highthroughput in vitro absorption, distribution, metabolism, and excretion (ADME 1 ) measurements alongside potency determinations. This early screening has occurred due to the increased compound synthesis from combinatorial chemistry, the increase in knowledge and availability of techniques for studying a compound's ADME properties, and, most importantly, the degree of attrition from unacceptable pharmacokinetics of drug candidates in the latter, more expensive stages of drug development (Rodrigues, 1994;Eddershaw and Dickins, 1999;Eddershaw et al, 2000;Thompson, 2001). While the incorporation of ADME assays into a screening strategy allows the generation of large amounts of data on many compounds, a rational drug metabolism strategy that arises from a sound understanding of the relevant in vitro techniques is preferable over a "brute force" approach of data generation.…”

mentioning

confidence: 99%

Flavin-Containing Monooxygenase Activity in Hepatocytes and Microsomes: In Vitro Characterization and In Vivo Scaling of Benzydamine Clearance

Fisher¹,

Yoon²,

Vaughn³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Liver microsomes, and more recently cryopreserved hepatocytes, are commonly used in the in vitro characterization of the metabolism of new xenobiotics. The flavin-containing monooxygenases (FMO) are a major nonP450 oxidase present in liver microsomes and hepatocytes. Since FMO is known to be thermally labile, and this enzyme may be involved in the metabolic clearance of some drugs, we sought to more completely characterize the metabolic competency of this enzyme in cryopreserved hepatocytes and in liver microsomes preincubated under various conditions using benzydamine as an in vitro and in vivo probe. The metabolism of benzydamine to its major metabolite, the N-oxide, is mediated by FMO3 in humans. We found that the in vitro microsomal t 1/2 was 70% longer when incubations were prewarmed at 37°C in the absence of NADPH compared with prewarming in the presence of an NADPH-regenerating system, and N-oxide formation was inhibited >99%. Interestingly, the in vivo clearance predicted from these incubations and from human hepatocytes overpredicted the observed clearance of benzydamine in humans (>10.5 versus 2.4 ml/min/kg). In contrast, rat hepatocytes successfully predicted rat in vivo benzydamine clearance to within ϳ30% (>68 versus 48 ml/min/kg). Benzydamine N-oxidation in liver microsomes from all common preclinical species demonstrated heat sensitivity. This information should be considered when extrapolating metabolism data of xenobiotics from these in vitro systems.

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confidence: 99%

Flavin-Containing Monooxygenase Activity in Hepatocytes and Microsomes: In Vitro Characterization and In Vivo Scaling of Benzydamine Clearance

Fisher¹,

Yoon²,

Vaughn³

et al. 2002

Drug Metab Dispos

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“…Examples of medicines that are derived from plants are aspirin (from willow tree bark) (2), digoxin (from the flower, Digitalis lanata) (3) and morphine (from opium) (4). Indeed, it is projected that in the industrialized nation, >60% of all medicines are either natural products or secondary metabolites thereof (5). Although there are challenges from different, novel drug discovery methods, natural products continue to produce additional clinical candidates and medicinal compounds.…”

Section: Sources Of Drugsmentioning

confidence: 99%

Drug development: Lessons from nature

2017

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Abstract. Natural products have been acknowledged for numerous years as a vital source of active ingredients in therapeutic agents. In particular, the use of active ingredients derived from plants for use in microbial natural products have long been used before the dawn of modern medicine. From ancient times, the efficacy of natural products has been associated with the chemistry, biochemistry and synthetic activities of natural products. Thus, with scientific advancement in modern molecular and cellular biology, analytical chemistry and pharmacology, the unique properties of these natural products are being harnessed in order to exploit the chemical and structural diversity and biodiversity of these types of products in relation to their therapeutic effect. Often, new molecules of interest in drug design units focus on the rearrangement of chemical entities or structural isomers of naturally occurring products in order to generate new molecules; these may be formulated into clinically useful therapies. Contents1. Introduction 2. Sources of drugs 3. Current uses of natural product drugs 4. Natural product drug development 5. Future directions for natural product drug discovery 6. Conclusions IntroductionA natural product is a chemical entity, formed by a naturally occurring living organism with pharmacological properties, which may contribute to vital drug discovery and design. The crude substance extracted from the body of medicinal plants, animals, microbes or microorganism fermentation broths contains unique and structurally diverse chemical components. Natural products have been vital in pharmaceutical and biotechnology industries, as a vast range of modern medicines are based upon either naturally occurring molecules, or derivatives of these. Generally, the therapeutic agents that are inhaled, ingested and injected are a mixture of complex therapeutic compounds. Sources of drugsThe complexity of the therapeutic agents depends on the mixture of chemicals prepared synthetically. Therapeutic agents are considered as natural, synthetic, or semi-synthetic dependent on the source from which they were generated (1). The natural environment remains a significant origin of novel therapeutic agent compounds. Natural therapeutic agents are prepared from compounds found occurring in nature, which contain active components in extract form created from sources, including plants, microbes, minerals and animals. The most dominant natural medicine source is plants, due to their chemical and structural diversity and the biodiversity of their components. Examples of medicines that are derived from plants are aspirin (from willow tree bark) (2), digoxin (from the flower, Digitalis lanata) (3) and morphine (from opium) (4). Indeed, it is projected that in the industrialized nation, >60% of all medicines are either natural products or secondary metabolites thereof (5). Although there are challenges from different, novel drug discovery methods, natural products continue to produce additional clinical candidates and medicinal comp...

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“…Biological processing of xenobiotics via ADME determines the feasibility of medicinal substances to become effective therapeutic agents (Eddershaw et al, 2000;Ekins et al, 2010;Lombardo & Waters, 2011;Ruiz-Garcia et al, 2008). Factors affecting the fate of xenobiotics may exist anywhere along the ADME process and may lead to a change of well designed and documented pharmacokinetic profiles of registered pharmaceuticals (Harris et al, 2003;.…”

Section: The Beauty and Odds Of Xenobiotics In The Biological Systemmentioning

confidence: 99%