[The inhibition of CYP2C9 isoenzyme in Cunninghamella blakesleeana AS 3. 910].
OBJECTIVE
To investigate the variation of CYP2C9 isoenzyme activity in the microbial model in response to inhibitors of CYP2C9.


METHODS
Using C. blakesleeana AS 3. 910 as a model strain, the impact of CYP2C9 inhibitors on the metabolites yields of CYP2C9 substrates was determined and the drug-drug interactions among CYP2C9 substrates were evaluated. Liquid chromatography-mass spectrometry was used to analyze biotransformation products.


RESULTS
Benzbromarone decreased the yield of 4'-hydroxytolbutamide from 100% to 14.5%; sulfaphenazole decreased the yield of O-demethylindomethacin from 75.2% to 9.9%; valproic acid decreased the yield of 4'-hydroxydiclofenac from 98.6% to 2.7%, separately. Tolbutamide, indomethacin and diclofenac interacted with each other, resulting in the decreased formation of metabolites catalyzed by CYP2C9.


CONCLUSIONS
Three CYP2C9 inhibitors inhibit the activity of CYP2C9 isoenzyme in C. blakesleeana AS 3. 910 differently, and there are drug-drug interactions among CYP2C9 substrates.
Lin
Li-Hong
LH
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Huang
Hai-Hua
HH
Zhang
Peng
P
Zhong
Da-Fang
DF
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001553:Benzbromarone / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D020093:Cunninghamella / Q000201:enzymology / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013379:Substrate Specificity; D013426:Sulfaphenazole / Q000494:pharmacology; D014044:Tolbutamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
C516573:4'-hydroxytolbutamide; D005656:Fungal Proteins; D007527:Isoenzymes; D013426:Sulfaphenazole; D004008:Diclofenac; D001553:Benzbromarone; D014635:Valproic Acid; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C108036:4'-hydroxydiclofenac; D007213:Indomethacin