Adverse reactions of imidazole antifungal agents: computer graphic studies of cytochrome P-450 interactions.
The imidazole antifungal agents give rise to adverse reactions and clinically relevant drug interactions. This is due to lack of specificity of the antifungal agents that interact avidly not only with the fungal but also with mammalian cytochrome P-450 proteins. A computer graphic technique capable of predicting the interaction of these structurally-related imidazoles with fungal and mammalian cytochrome P-450 proteins is described. This prediction is achieved by comparing the molecular conformation of these drugs with lanosterol, the substrate of the fungal cytochrome P-450, and with phenobarbitone, an inducing agent of a family of mammalian cytochrome P-450, toward which the antifungal agents show highest inhibitory activity.
Lewis
D F
DF
Department of Biochemistry, University of Surrey, Guildford, United Kingdom.
Rodrigues
A D
AD
Ioannides
C
C
Parke
D V
DV
D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects* / Q000378:metabolism; D003022:Clotrimazole / Q000009:adverse effects; D003196:Computer Graphics; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007093:Imidazoles / Q000009:adverse effects* / Q000378:metabolism; D007654:Ketoconazole / Q000009:adverse effects; D008825:Miconazole / Q000009:adverse effects; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D003022:Clotrimazole; D007654:Ketoconazole