Advertisement

Agents and Actions

, 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

Abstract

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.

Keywords

Complex Formation Phenobarbital Parent Compound Diphenhydramine Hydrophobic Pocket 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    M. R. Franklin,Inhibition of mixed-function oxidations by substrates forming reduced cytochrome P-450 metabolic-intermediate complexes. Pharmacol. Ther. Part A3, 227–245 (1977).Google Scholar
  2. [2]
    A. Bast, E. M. Savenije-Chapel and J. Noordhoek,Relationship between molecular structure and cytochrome P-450-metabolic intermediate complex formation. J. Pharm. Sci.73, 953–956 (1984).PubMedGoogle Scholar
  3. [3]
    U. B. Paulsen-Sörman, K.-H. Jönssen and B. G. A. Lindeke,Cytochrome P-455 nm complex formation in the metabolism of phenylalkylamines 8. Stereoselectivity in metabolic intermediary complex formation with a series of chiral 2-substituted 1-phenyl-2-aminoethanes. J. Med. Chem.27, 342–346 (1984).PubMedGoogle Scholar
  4. [4]
    A. Bast and J. Noordhoek,Spectral interactions of orphenadrine and its metabolites with oxidized and reduced hepatic microsomal cytochrome P-450 in the rat. Biochem. Pharmacol.31, 2745–2753 (1982).PubMedGoogle Scholar
  5. [5]
    A. Bast, E. M. Savenije-Chapel, F. A. A. van Kemenade, L. W. C. Scheefhals and J. Noordhoek,Effect of multiple administration of orphenadrine or mono-N-desmethylorphenadrine on cytochrome P-450 catalyzed reactions in the rat. Arch. Toxicol.54, 131–137 (1983).PubMedGoogle Scholar
  6. [6]
    M. Hirata, B. Lindeke and S. Orrenius,Cytochrome P-450 product complexes and glutathione consumption produced in isolated hepatocytes by norbenzphetamine and its N-oxidized congeners. Biochem. Pharmacol.28, 479–484 (1979).PubMedGoogle Scholar
  7. [7]
    D. Larrey, M. Tinel, P. Letteron, J. Geneve, V. Descatoire and D. Pessayre,Formation of an inactive cytochrome P-450Fe(II)-metabolite complex after administration of amiodarone in rats, mice and hamsters. Biochem. Pharmacol.35, 2213–2220 (1986).PubMedGoogle Scholar
  8. [8]
    A. Bast, F. A. A. van Kemenade, E. M. Savenije-Chapel and J. Noordhoek,Product inhibition in orphenadrine metabolism as a result of a stable cytochrome P-450-metabolic intermediate complex formed during the disposition of mono-N-desmethylorphenadrine (tofenacine) in the rat. Res. Commun. Chem. Pathol. Pharmacol.40, 391–403 (1983).PubMedGoogle Scholar
  9. [9]
    R. F. Rekker and H. M. de Kort,The hydrophobic fragmental constant; an extension to a 1000 data point set. Eur. J. Med. Chem.14, 479–488 (1979).Google Scholar
  10. [10]
    L. K. Pershing and M. R. Frankling,Cytochrome P-450 metabolic-intermediate complex formation and induction by macrolide antibiotics; a new class of agents. Xenobiotica12, 687–699 (1982).PubMedGoogle Scholar
  11. [11]
    M. R. Franklin, C. R. Wolf, C. Serabjit-Singh, R. M. Philpot,Quantitation of two forms of pulmonary cytochrome P-450 in microsomes, using substrate specificities. Mol. Pharmacol.17, 415–420 (1980).PubMedGoogle Scholar
  12. [12]
    C. Hansch,quantitative relationships between lipophilic character and drug metabolism. Drug Metab. Rev.1, 1–13 (1972).Google Scholar
  13. [13]
    D. Larrey, M. Tinel and D. Pessayre,Formation of inactive cytochrome P-450Fe(II) metabolic complexes with several erythromycin derivatives but not with josamycin and midecamycin in rats. Biochem. Pharmacol.32, 1487–1493 (1983).PubMedGoogle Scholar

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

Personalised recommendations