CPSA Digest 2001

Proceedings -Thursday, October 11, 2001

ThOA2

Metabolism Models for Drug Discovery - Metabolite ID, Profiling, Stability and Inhibition

Background:
The general goals of drug discovery are to:

• Rationally discover and develop molecules with drug-like attributes
• Improve the quality of drug candidates
• Decrease compound attrition rate in drug development
• Optimize probability for success in clinical therapy The eventual goal of drug discovery is to get a promising lead drug into the clinic for evaluation.

Premise:
Both in vitro and in vivo tools have been widely used to optimize biopharmaceutical and pharmacokinetic properties of drug candidates. Various screens have been developed to assess such properties in a high throughput mode.

The various in vitro tools in use as screens include the following: Solubility Lipophilicity Permeability (CACO-2, PAMPA, etc.) Protein binding Stability, physicochemical Stability, biological Plasma blood cell culture Recombinant enzymes Microsomes, cytosol, S9 fractions Isolated cells (hepatocytes) Tissue slices (liver slices) In situ (sections of GIT, e.g., jejunum) Organ perfusion CYP450 enzyme modulation Expressed isozymes, microsomes, hepatocytes Probe substrate assay for inhibition/induction Western blot gel electrophoresis Quantitative PCR Drug metabolism gene chip

Some of the in vivo tools in use as screens include the following: Pharmacokinetics (intravenous and oral) Bioavailability Relationship between pharmacokinetics and pharmacodynamics Dose proportionality Species differences Species similarities Scaling and prediction of human parameters

How ADME data are used in the drug discovery phase:

• ADME data are used as a filter to aid in the selection process of a drug candidate
• ADME data are used to solve pharmacokinetic problems‹those problems previously identified or anticipated
• ADME data are used prospectively and results help to optimize molecular design

The process of Mechanism-Based ADME Optimization used at Aventis as their "lead selection strategy" was presented.

References

H. van de Waterbeemd, D.A. Smith, K. Beaumont and D.K. Walker, "Property-based design: optimization of drug absorption and pharmacokinetics," J.Med.Chem. 44 (2001) 1313-1333.

T Kennedy, "Causes of Attrition," Drug Discovery Today 2, 436-444 (1997).

Return to Proceedings »