Induction of drug metabolising enzymes: pharmacokinetic and toxicological consequences in humans

Clin Pharmacokinet. 2000 Jun;38(6):493-504. doi: 10.2165/00003088-200038060-00003.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug-Related Side Effects and Adverse Reactions
  • Enzyme Induction / drug effects*
  • Humans
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics*

Substances

  • Pharmaceutical Preparations