Revisiting the metabolism of ketoconazole using accurate mass.
The microsomal metabolism of ketoconazole is revisited using accurate mass LC/MS(n) and deuterium labelling. Structures for sixteen metabolites are proposed from rat and human microsomal metabolism of commercial ketoconazole. Thirteen of the proposed structures are well determined and consistent with all data; five of the proposed structures are less certain. Ten of the metabolites are described for the first time. Reaction phenotyping shows that most of the metabolites arise from CYP3A4, the enzyme known to be well inhibited by ketoconazole.
Fitch
William L
WL
Department of Drug Metabolism and Pharmacokinetics, Roche Palo Alto, Palo Alto, CA 94304, USA. bill.fitch@roche.com
Tran
Thuy
T
Young
May
M
Liu
Liling
L
Chen
Yuan
Y
D000818:Animals; D001711:Biotransformation; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D041961:Deuterium Exchange Measurement; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D015394:Molecular Structure; D008970:Molecular Weight; D051381:Rats; D053719:Tandem Mass Spectrometry
D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole