Methods for Predicting Drug Metabolism

2 Statistical, Pharmacophore, and Homology Models and Crystal Structures of Drug-Metabolizing Enzymes 

4 Databases and Rule-Based Approaches for Metabolism Prediction 

Computer Applications in Pharmaceutical Research and Development, Edited by Sean Ekins. ISBN 0-471-73779-8 Copyright 2006 John Wiley Sons, Inc. 

2 STATISTICAL, PHARMACOPHORE, AND HOMOLOGY MODELS AND CRYSTAL STRUCTURES OF DRUG-METABOLIZING ENZYMES 

In the 1960s it was discovered that a mathematical model could describe the relationship between simple calculated molecular properties for a series of 

---

Ekins S. Computer methods for predicting drug metabolism. In Ekins S, editor, Computer applications in pharmaceutical research and development. Hoboken, NJ Wiley, 2006. p. 445-68. 

Jolivette, L.J. and Ekins, S. (2007) Methods for predicting human drug metabolism. Advances in Clinical Chemistry, 43, 131-176. 

Pelander, A., Tyrkko, E., and Ojanpera, I., In silico methods for predicting metabolism and mass fragmentation applied to quetiapine in liquid chromatography/time-of-flight mass spectrometry urine drug screening, Rapid Commun, Mass Spectrom., 23(4), 506, 2009. 

Gibbs, J. P., Hyland, R., and Youdim, K. (2006) Minimizing polymorphic metabolism in drug discovery evaluation of the utility of in vitro methods for predicting pharmacokinetic consequences associated with CYP2D6 metabolism. Drug Metab. Dispos. 34, 1516-1522. 

For more on the merits and demerits of microsomes, cytosol, S9, and other metabolizing systems in predicting drug metabolism, see Brandon, E.F.A., et al. An update on in vitro test methods in human hepatic drug biotransformation research Pros and cons. Toxicol. Appl. Pharmacol. 2003, 189, 231-246. 

Shibata Y, Takahashi H, Ishii Y.A convenient in vitro screening method for predicting in vivo drug metabolic clearance using isolated hepatoc 4 es suspended in serum. Drug Metab Dispos 2000 28 1518-1523. 

Houston, J.B. and Galetin, A. (2008) Methods for predicting in vivo pharmacokinetics using data from in vitro assays. Current Drug Metabolism, 9,940-951. 

Methods for quantifying both the transcellular diffusion and concurrent metabolism of drugs and the unusual transcellular diffusion of membrane-interactive molecules coupled with the influence of protein binding are described in detail. To demonstrate the utility of cultured cell monolayers as a tool for basic science investigations, a subsection is devoted to the elucidation of rate-determining steps and factors in the passive diffusion of peptides across biological membranes. The chapter concludes with a discussion on the judicious use of in vitro cell monolayer results to predict in vivo results. 

Zhou, D., Afzelius, L., Grimm, S.W., Andersson, T.B., Zauhar, R.J. and Zamora, I. (2006) Comparison of methods for the prediction of the metabolic sites for CYP3A4-mediated metabolic reactions. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 976-983. 

---