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

Article Details

Citation

Tassaneeyakul W, Birkett DJ, Miners JO

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

Xenobiotica. 1998 Mar;28(3):293-301. doi: 10.1080/004982598239579 .

PubMed ID
9574817 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
BifonazoleCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
BromazepamCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
ChlorpromazineCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
ClonazepamCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
ClotrimazoleCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
DesipramineCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
DiazepamCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
EconazoleCytochrome P450 2E1ProteinHumans
No
Inhibitor
Details
FlunitrazepamCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
FlurazepamCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
ItraconazoleCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
MiconazoleCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
NitrazepamCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
NortriptylineCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
Drug Reactions
Reaction
Details
Drug Interactions
DrugsInteraction
Acetaminophen
Niacin
The metabolism of Acetaminophen can be decreased when combined with Niacin.
Acetaminophen
Diosmin
The metabolism of Acetaminophen can be decreased when combined with Diosmin.
Acetaminophen
Mitoxantrone
The metabolism of Acetaminophen can be increased when combined with Mitoxantrone.
Aldesleukin
Phenobarbital
The metabolism of Aldesleukin can be decreased when combined with Phenobarbital.
Aminophylline
Carvedilol
The metabolism of Aminophylline can be decreased when combined with Carvedilol.
Aminophylline
Trimethadione
The metabolism of Aminophylline can be decreased when combined with Trimethadione.
Aminophylline
Ethosuximide
The metabolism of Aminophylline can be decreased when combined with Ethosuximide.
Aminophylline
Theophylline
The metabolism of Aminophylline can be decreased when combined with Theophylline.
Aminophylline
Chlorzoxazone
The metabolism of Aminophylline can be decreased when combined with Chlorzoxazone.
Aminophylline
Enflurane
The metabolism of Aminophylline can be decreased when combined with Enflurane.
Interactions
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