Prediction of Human Drug Metabolizing Enzyme Induction

Mankowski, Dayna C.; Ekins, Sean
October 2003
Current Drug Metabolism;Oct2003, Vol. 4 Issue 5, p381
Academic Journal
New chemical entities are routinely screened in vitro and in vivo for their ability to induce cytochrome P450s (CYP), other drug-metabolizing enzymes and possibly transporters in an attempt to more accurately predict clinical parameters such as drug-drug interactions and clearance in humans. Some of these potential therapeutic agents can cause induction of the metabolism of another molecule or auto-induction thereby increasing their own metabolism and elimination, as well as potentially any molecules metabolized by the same enzyme(s). Key CYPs in the 1A, 2B, 2C, and 3A families have all been shown to be inducible. It would be clearly advantageous to know the potential for a compound to induce drug metabolizing enzymes or transporters prior to clinical development, and many in vitro systems have been developed for this purpose. Newer computational technologies are also being applied in order to attempt to predict induction from the molecular structure alone before a molecule is even synthesized or tested. This review will cover the various in vitro and in silico methods developed for prediction of key inducers of CYPs and other proteins, as well as the limitations of such technologies and applications in the future.


Related Articles

  • Electronic and Structural Aspects of P450-Mediated Drug Metabolism. Lewis, David F. V.; Ito, Yuko; Lake, Brian G. // Drug Metabolism Letters;Apr2009, Vol. 3 Issue 2, p87 

    From a consideration of first principles for enzymes kinetics, we have employed theoretical methods which enable one to analyse the kinetics of cytochrome P450-mediated reactions which have been based on the known physicochemical principles underlying the majority of chemical or enzymatic...

  • Kidney CYP450 Enzymes: Biological Actions Beyond Drug Metabolism. Zhao, X.; Imig, J.D. // Current Drug Metabolism;Feb2003, Vol. 4 Issue 1, p73 

    Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs), their corresponding dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE). These arachidonic acid metabolites are involved in...

  • Human Cytochromes P450 Associated with the Phase 1 Metabolism of Drugs and other Xenobiotics: A Compilation of Substrates and Inhibitors of the CYP1, CYP2 and CYP3 Families. Lewis, David F.V. // Current Medicinal Chemistry;Oct2003, Vol. 10 Issue 19, p1955 

    This review represents a compilation of typical substrates and inhibitors for human cytochrome P450 (CYP) enzymes that are involved in drug metabolism, specifically those from the CYP1, CYP2 and CYP3 families. Relatively recent literature on substrates and inhibitors has been collected and the...

  • The Effect of Psoralens on Hepatic and Cutaneous Drug Metabolizing Enzymes and Cytochrome P-450. Bickers, David R.; Mukhtar, Hasan; Molica Jr., S. J.; Pathak, Madhu A. // Journal of Investigative Dermatology;Sep82, Vol. 79 Issue 3, p201 

    Psoralens are tricyclic furocoumarins with potent photosensitizing properties in the skin and are now widely used in the treatment of several dermatologic diseases. In this study the effect of 3 different psoralens 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and isopsoralen on...

  • Drugs Behave as Substrates, Inhibitors and Inducers of Human Cytochrome P450 3A4. Shu-Feng Zhou // Current Drug Metabolism;May2008, Vol. 9 Issue 4, p310 

    Human cytochrome P450 (CYP) 3A4 is the most abundant hepatic and intestinal phase I enzyme that metabolizes approximately 50% marketed drugs. The crystal structure of bound and unbound CYP3A4 has been recently constructed, and a small active site and a peripheral binding site are identified. A...

  • Many Drugs and Phytochemicals Can Be Activated to Biological Reactive Intermediates. Johnson, William W. // Current Drug Metabolism;May2008, Vol. 9 Issue 4, p344 

    The metabolism of drugs and other xenobiotics is exemplified by cytochrome P450-mediated oxidation to more hydrophilic compounds. Enzymatic oxidation of some functional groups, however, can result in transient reactive intermediates -- a transformation that is common in nature. Some drugs and...

  • Cytochrome P450-Activated Prodrugs: Targeted Drug Delivery. Huttunen, Kristina M.; Mähönen, Niina; Raunio, Hannu; Rautio, Jarkko // Current Medicinal Chemistry;2008, Vol. 15 Issue 23, p2346 

    Cytochrome P450 (CYP) enzymes are a superfamily of heme containing proteins that catalyze xenobiotic metabolism phase I reactions. Oxidation reactions are the most common CYP-catalyzed reactions for both endogenous substrates and exogenous compounds, including drugs, although CYP enzymes are...

  • A support vector machine approach to classify human cytochrome P450 3A4 inhibitors. Kriegl, Jan; Arnhold, Thomas; Beck, Bernd; Fox, Thomas // Journal of Computer-Aided Molecular Design;Mar2005, Vol. 19 Issue 3, p189 

    The cytochrome P450 (CYP) enzyme superfamily plays a major role in the metabolism of commercially available drugs. Inhibition of these enzymes by a drug may result in a plasma level increase of another drug, thus leading to unwanted drug–drug interactions when two or more drugs are...

  • Assessment of Cytochrome P450 Enzyme Inhibition and Inactivation in Drug Discovery and Development. Nettleton, David O.; Einolf, Heidi J. // Current Topics in Medicinal Chemistry;Feb2011, Vol. 11 Issue 4, p382 

    Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics