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, Volume 30, Issue 1–2, pp 161–165 | Cite as

Cytochrome P-450 metabolic-intermediate complex formation with a series of diphenhydramine analogues

  • A. Bast
  • A. J. Valk
  • H. Timmerman
Histamine Receptors and Antihistamines


A series of diphenhydramine analogues have been studied with regard to their formation of a metabolic intermediate (MI) during their biotransformation in phenobarbital induced rat hepatic microsomes. The MI forms a complex with reduced cytochrome P-450. MI complexation of cytochrome P-450 may result in drug-drug interactions and/or in cumulation of the parent compound. The extent of MI complex formation could be correlated with the lipophilicity of the substrates in a parabolic manner. A hydrophobic pocket of limited dimensions in cytochrome P-450 for the N-alkyl substituent of the substrates can be assumed. Moreover our data indicate a role for the O-atom in the diphenhydramine analogues for the interaction with cytochrome P-450.


Complex Formation Phenobarbital Parent Compound Diphenhydramine Hydrophobic Pocket 


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Copyright information

© Birkhäuser Verlag 1990

Authors and Affiliations

  • A. Bast
    • 1
  • A. J. Valk
    • 1
  • H. Timmerman
    • 1
  1. 1.Department of Pharmacochemistry, Faculty of ChemistryVrije UniversiteitAmsterdamThe Netherlands

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