Enzyme Induction or Inhibition

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Is the drug likely to he co-prescribed with a drug of narrow therapeutic index For example, a drug for angina, cardiac failure or an antiarrhythmic agent is likely to be co-prescribed with warfarin. If there is any evidence of enzyme induction or inhibition, a clinical study with warfarin may be required. 

Figure 2 The impact of genetic polymorphisms (the UM, EM, IM, and PM genotypes) and the corresponding impact of enzyme induction or inhibition on exposure to a drug. Abbreviations UM, ultrarapid metabolizer EM, extensive metabolizer IM, intermediate metabolizer PM, poor metabolizer.

Drugs that cause induction or inhibition of enzymes may affect the metabolism of concomitantly administered drugs, as well as of hormones and other endogenous substances. For this reason, such properties are considered undesirable and sometimes they might constitute sufficient reason to discontinue drug development. At the very least, studies will be required to assess the magnitude of effect of likely interactions. Metabolic and toxicity studies in animals will usually provide the basis for suspicion, and studies in human liver slices, cultured hepatocytes and microsomal preparations can be extremely valuable in establishing metabolic pathways and the likelihood of enzyme induction or inhibition in man. There have been some important developments in this field in recent years and it is now possible to identify ... 

Multiple-dose pharmacokinetics to assess accumulation or changes in clearance caused by enzyme induction or inhibition... 

Peak level, half-life, and so forth Plasma protein binding Tissue distribution/accumulation Enzyme induction or inhibition Metabolites... 

Furthermore, nonester-type drugs, especially lidocaine derivatives, also are known to be more prone to enzyme induction or inhibition of other medications (e.g., cimetidine and barbiturates). 

The pharmacokinetics and metabolism of phenazone (largely used as an investigational marker drug of enzyme induction or inhibition) were studied in two groups of patients with prostate cancer before and after they took either bicalutamide 50 mg daily (7 patients) or 150 mg daily (11 patients) for 12 weeks. Small changes in the phenazone pharmacokinetics were found (half-life reduced by 16.3% with the 50 mg bicalutamide dos-... 

Enzyme induction or inhibition Diet and nutrition Dose and timing Genetics. 

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