Assessment of enzyme induction and enzyme inhibition in humans: toxicological implications.

1. The principal methods used for the assessment of enzyme induction and enzyme inhibition are measurement of the pharmacokinetics of a model compound (probe drug), analysis of drug metabolism in vitro, and determination of changes in the disposition of, and endogenous substrate for, the enzyme of interest. 2. Probe drugs that have been used for this purpose include antipyrine, aminopyrine, tolbutamide, caffeine, theophylline, warfarin, oxazepam and paracetamol. Measurement of the excretion of metabolites of cortisol and oestradiol, which are endogenous substrates for cytochrome P450 IIIA enzymes, provides a non-invasive means of assessing enzyme induction or inhibition. 3. Combined pharmacokinetic/pharmacodynamic studies are required to assess the pharmacological relevance of either induction or inhibition of the enzymes involved in drug metabolism. 4. At present it is difficult to assess the toxicological implications of enzyme induction and inhibition in man. Safe probe drugs are required for the enzymes primarily responsible for drug detoxication, such as epoxide hydrolase and glutathione transferase, in order to identify individuals particularly at risk.