In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.
Article Details
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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
Drug Enzyme Kind Organism Pharmacological Action Actions Armodafinil Cytochrome P450 1A2 Protein Humans UnknownInducerDetails Armodafinil Cytochrome P450 2B6 Protein Humans UnknownInducerDetails Armodafinil Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails Armodafinil Cytochrome P450 2C9 Protein Humans NoInhibitorDetails Armodafinil Cytochrome P450 3A4 Protein Humans UnknownInducerDetails Armodafinil Cytochrome P450 3A5 Protein Humans UnknownInducerDetails Modafinil Cytochrome P450 2B6 Protein Humans UnknownInhibitorInducerDetails Modafinil Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails Modafinil Cytochrome P450 2C9 Protein Humans UnknownInhibitorInducerDetails Modafinil Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Modafinil Cytochrome P450 3A5 Protein Humans NoSubstrateInducerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAbemaciclibModafinil The metabolism of Abemaciclib can be increased when combined with Modafinil. AbemaciclibArmodafinil The metabolism of Abemaciclib can be increased when combined with Armodafinil. AbrocitinibArmodafinil The metabolism of Abrocitinib can be decreased when combined with Armodafinil. AbrocitinibModafinil The metabolism of Abrocitinib can be decreased when combined with Modafinil. AcalabrutinibModafinil The metabolism of Acalabrutinib can be increased when combined with Modafinil. AcalabrutinibArmodafinil The metabolism of Acalabrutinib can be increased when combined with Armodafinil. AcenocoumarolModafinil The metabolism of Acenocoumarol can be increased when combined with Modafinil. AcenocoumarolArmodafinil The metabolism of Acenocoumarol can be increased when combined with Armodafinil. AlbendazoleModafinil The metabolism of Albendazole can be decreased when combined with Modafinil. AlbendazoleArmodafinil The metabolism of Albendazole can be decreased when combined with Armodafinil. 
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