Inhibition of human hepatic cytochrome P4502E1 by azole antifungals, CNS-active drugs and non-steroidal anti-inflammatory agents.

1. The capacity of a number of antifungal azoles, CNS-active drugs (anticonvulsants, antidepressants, antipsychotics and benzodiazepine hypnosedative-anxiolytics) and nonsteroidal anti-inflammatory agents (NSAIDs) to inhibit human liver microsomal 4-nitrophenol (4NP) hydroxylation, a marker of CYP2E1 activity, was investigated. 2. The imidazoles bifonazole, clotrimazole, econazole and miconazole were un- or non-competitive inhibitors of 4NP hydroxylation, with apparent Ki values ranging from 4 to 25 microM. Fluonazole, itraconazole and ketoconazole caused minor or negligible inhibition. 3. Of the CNS-active drugs screened, significant inhibition occurred only with tricyclic antidepressants, phenothiazine antipsychotics and two benzodiazepines (flurazepam and medazepam). Un- or non-competitive inhibition was similarly observed for the tricyclic antidepressants, phenothiazines, flurazepam and medazepam, with apparent Ki values ranging from 175 to 1000 microM. 4. Diclofenac and flufenamic acid were the only NSAIDs found to inhibit 4NP hydroxylation substantially; kinetic analysis was suggestive of activation-inhibition phenomena. 5. These data indicate that, although not substrates for CYP2E1, some clinically used drugs have the capacity to inhibit this enzyme and hence have the potential to modulate the toxicity of non-drug xenobiotics metabolized by CYP2E1.