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Clinical Pharmacokinetics

, Volume 38, Issue 6, pp 493–504 | Cite as

Induction of Drug Metabolising Enzymes

Pharmacokinetic and Toxicological Consequences in Humans
  • Uwe FuhrEmail author
Review Article Concepts

Abstract

Currently, 5 different main mechanisms of induction are distinguished for drug-metabolising enzymes. The ethanol type of induction is mediated by ligand stabilisation of the enzyme, but the others appear to be mediated by intracellular ‘receptors’. These are the aryl hydrocarbon (Ah) receptor, the peroxisome proliferator activated receptor (PPAR), the constitutive androstane receptor (CAR, phenobarbital induction) and the pregnane X receptor [PXR, rifampicin (rifampin) induction].

Enzyme induction has the net effect of increasing protein levels. However, many inducers are also inhibitors of the enzymes they induce, and the inductive effects of a single drug may be mediated by more than one mechanism. Therefore, it appears that every inducer has its own pattern of induction; knowledge of the main mechanism is often not sufficient to predict the extent and time course of induction, but may serve to make the clinician aware of potential dangers.

The possible pharmacokinetic consequences of enzyme induction depend on the localisation of the enzyme. They include decreased or absent bioavailability for orally administered drugs, increased hepatic clearance or accelerated formation of reactive metabolites, which is usually related to local toxicity. Although some severe drug-drug interactions are caused by enzyme induction, most of the effects of inducers are not detected in the background of nonspecific variation. For any potent inducer, however, its addition to, or withdrawal from, an existing drug regimen may cause pronounced concentration changes and should be done gradually and with appropriate monitoring of therapeutic efficacy and adverse events.

The toxicological consequences of enzyme induction in humans are rare, and appear to be mainly limited to hepatoxicity in ethanol-type induction.

Keywords

Verapamil Isoniazid Phenobarbital Tacrine Enzyme Induction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The data were presented in part at the 7th European ISSX Meeting in Budapest, August 1999. The ISSX also printed a manuscript of this presentation as a ‘Short Course Manual’ (ISBN 9-634-20610-7) which was made available at the meeting.

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Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Institute for Pharmacology, Clinical PharmacologyUniversity of CologneCologneGermany

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