High-throughput screening approaches for investigating drug metabolism and pharmacokinetics.
1. High-throughput screening approaches have been adopted throughout the pharmaceutical industry to aid in the rapid discovery of new chemical entities. Because it is now well recognized that the selection of a robust candidate requires a balance of potency, safety and pharmacokinetics, the role of drug metabolism departments has widened from their traditional one of supporting drug development to include the screening of compounds during the discovery process. To put drug metabolism and pharmacokinetic (DMPK) studies in context, the evolving role of DMPK screening in the drug discovery strategy of pharmaceutical companies will be discussed and a generalized approach will be presented. 2. With the increasing numbers of compounds requiring screening, DMPK optimization methods have had to be adapted for high throughput. There have been many developments in this field over the past decade and this review will focus on the high-throughput DMPK screening methodologies used today and in the recent past. 3. In vitro and in silico (computer-based) methods have proven most amenable to high-throughput approaches and these will firm the bulk of the review, but some advances with in vivo methods will also be discussed. As there has been a vast increase in published material on the topic of high-throughput DMPK methodologies in the past 10 years, it would be impossible to cover every method in detail, so this review will concentrate on the key areas and refer the reader to other, more detailed reviews wherever possible. 4. Most high-throughput methods would not be possible without the enabling technologies of computing, automation, new sample preparation technologies, and highly sensitive and selective detection systems, and these will also be reviewed. 5. The advantages and disadvantages of the screening methods will be presented, in particular the issue of handling the false-positives and -negatives that arise. 6. In concluding the review, future developments in this field will be discussed along with key issues that will need to be addressed.
Roberts
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Drug Metabolism and Pharmacokinetics, Celltech Research and Development Ltd, Great Abington, Cambridge, UK. simon.roberts@celltechgroup.com
D000042:Absorption; D000818:Animals; D001693:Biological Transport, Active; D001798:Blood Proteins / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry; D004355:Drug Stability; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008567:Membranes, Artificial; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011485:Protein Binding
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations