Induction of drug metabolising enzymes - Pharmacokinetic and toxicologicalconsequences in humans

Currently, 5 different main mechanisms of induction are distinguished for d rug-metabolising enzymes. The ethanol type of induction is mediated by liga nd stabilisation of the enzyme, but the others appear to be mediated by int racellular 'receptors'. These are the aryl hydrocarbon (Ah) receptor, the p eroxisome proliferator activated receptor (PPAR), the constitutive androsta ne 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 induc tive effects of a single drug may be mediated by more than one mechanism. T herefore, it appears that every inducer has its own pattern of induction; k nowledge of the main mechanism is often not sufficient to predict the exten t and time course of induction, but may serve to make the clinician aware o f potential dangers. The possible pharmacokinetic consequences of enzyme induction depend on the localisation of the enzyme, They include decreased or absent bioavailabili ty for orally administered drugs, increased hepatic clearance or accelerate d formation of reactive metabolites, which is usually related to local toxi city. Although some severe drug-drugs interactions are caused by enzyme ind uction, 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 concentr ation 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.