In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.

Article Details

Citation

Robertson P, DeCory HH, Madan A, Parkinson A

In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.

Drug Metab Dispos. 2000 Jun;28(6):664-71.

PubMed ID
10820139 [ View in PubMed
]
Abstract

The ability of modafinil to affect human hepatic cytochrome P450 (CYP) activities was examined in vitro. The potential for inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 by modafinil (5-250 microM) was evaluated with pooled human liver microsomes. Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19. Modafinil inhibited the 4'-hydroxylation of S-mephenytoin, a marker substrate for CYP2C19, reversibly and competitively with a K(i) value of 39 microM, which approximates the steady-state C(max) value of modafinil in human plasma at a dosage of 400 mg/day. No irreversible inhibition of any CYP enzyme was observed, and there was no evidence of metabolism-dependent inhibition. The potential for induction of CYP activity was evaluated by exposing primary cultures of human hepatocytes to modafinil (10-300 microM). Microsomes were then prepared and assayed for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 activities. The mean activities of microsomal CYP1A2, CYP2B6, and CYP3A4/5 from modafinil-treated hepatocytes were higher (up to 2-fold) than those in the solvent-treated controls but were less than those produced by reference inducers of these enzymes. At high concentrations of modafinil (>/=100 microM), the mean activity of CYP2C9 was decreased (up to 60%) relative to that in the solvent controls. Overall, modafinil was shown to have effects on human hepatic CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 activities in vitro. Although effects obtained in vitro are not always predictive of effects in vivo, such results provide a rational basis for understanding drug-drug interactions that are observed clinically and for planning subsequent investigations.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
ArmodafinilCytochrome P450 1A2ProteinHumans
Unknown
Inducer
Details
ArmodafinilCytochrome P450 2B6ProteinHumans
Unknown
Inducer
Details
ArmodafinilCytochrome P450 2C19ProteinHumans
Unknown
Inhibitor
Details
ArmodafinilCytochrome P450 2C9ProteinHumans
No
Inhibitor
Details
ArmodafinilCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
ArmodafinilCytochrome P450 3A5ProteinHumans
Unknown
Inducer
Details
ModafinilCytochrome P450 2B6ProteinHumans
Unknown
Inhibitor
Inducer
Details
ModafinilCytochrome P450 2C19ProteinHumans
Unknown
Inhibitor
Details
ModafinilCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Inducer
Details
ModafinilCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
ModafinilCytochrome P450 3A5ProteinHumans
No
Substrate
Inducer
Details
Drug Interactions
DrugsInteraction
Abemaciclib
Modafinil
The metabolism of Abemaciclib can be increased when combined with Modafinil.
Abemaciclib
Armodafinil
The metabolism of Abemaciclib can be increased when combined with Armodafinil.
Acalabrutinib
Modafinil
The metabolism of Acalabrutinib can be increased when combined with Modafinil.
Acalabrutinib
Armodafinil
The metabolism of Acalabrutinib can be increased when combined with Armodafinil.
Acenocoumarol
Modafinil
The metabolism of Acenocoumarol can be increased when combined with Modafinil.
Acenocoumarol
Armodafinil
The metabolism of Acenocoumarol can be increased when combined with Armodafinil.
Albendazole
Modafinil
The metabolism of Albendazole can be decreased when combined with Modafinil.
Albendazole
Armodafinil
The metabolism of Albendazole can be decreased when combined with Armodafinil.
Alectinib
Modafinil
The metabolism of Alectinib can be increased when combined with Modafinil.
Alectinib
Armodafinil
The metabolism of Alectinib can be increased when combined with Armodafinil.
Interactions
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