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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
Download (direct link): pharmacokinetiksmedicanalchemistri2001.pdf
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9.6
Elimination Half-life
The relationship between elimination half-life (t1/2) and body weight across species results in poor correlation, most probably because of the hybrid nature of this parameter [27]. A better approach may be to estimate volume of distribution and clearance by the most appropriate method and then estimate half-life indirectly from the relationship:
t1/2 = (0.693 • Vd)/Cls
(9.5)
132
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Pharmacokinetics and Metabolism in Drug Design 133 Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman I
Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)
10
High(er) Throughput ADME Studies
Abbreviations
ADME Absorption, distribution, metabolism, excretion
CYP3A4 Cytochrome P450 3A4
DMPK Drug metabolism and pharmacokinetics
HTS High throughput screening
MTS Medium throughput screening
P-gp P-glycoprotein
PK Pharmacokinetics
UHTS Ultra-high throughput screening
10.1
The HTS Trend
New approaches to medicinal chemistry such as parallel synthesis and combinatorial chemistry strategies [1] and refinement of high throughput screening in biology place Drug Discovery at a crossroads. Will traditional rationale medicinal chemistry continue as the cornerstone of how we discover drugs or will shear numbers of compounds be the winning formula. High compound numbers are essential whatever the eventual scenario to ensure that early lead matter is available. The size of compound files of the future, millions of compounds, means informatics and automation are key ingredients for a successful drug discovery organization [2]. How much drug metabolism needs to adapt is part of the question. Clearly many of the in vitro approaches can be automated and thus increase efficiencies. These systems are equally adaptable to screening a file or providing fast turnaround on newly synthesized products of a rationale discovery programme. Both approaches are being pursued. This chapter discusses the place of ADME screens and describes some of the recent developments which give insight into how medicinal chemistry, in a not too far future, may benefit.
134 | 10 High(er) Throughput ADME Studies
10.2
Drug Metabolism and Discovery Screening Sequences
The development of higher throughput approaches in ADME studies is driven by the advances in high-speed chemistry and pharmacological screening [3], a view of the future where many more compounds would need to be screened, and the availability of the technology. Departments of Drug Metabolism and Pharmacokinetics in the pharmaceutical industry are organizing themselves for the rapid evaluation of large numbers of compounds [4-8]. Higher throughput can move a screening approach up the traditional sequence, provide more comprehensive data on a single compound, or just screen more compounds or even files. The pre-ADME days of Discovery had screening sequences based on an in vitro functional response often followed by an oral rodent pharnmacodynamic model. The advent of ADME, cloned receptors etc., has led to the hierarchical sequence shown in Figure 10.1. Higher throughput could allow a parallel process, which collects large amounts of in vitro pharmacology and ADME data as the primary stage.
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