Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates.
Racemic ketoconazole (KTZ) was the first orally active azole antifungal agent used in clinical practice and has become widely used in the treatment of mucosal fungal infections associated with AIDS immunosuppression and cancer chemotherapy. However, the use of KTZ has been limited because of adverse drug-drug interactions. KTZ blocks ergosterol biosynthesis by inhibiting the fungal cytochrome P450 (CYP51). KTZ is also a potent inhibitor of human cytochrome P450 3A4 (CYP3A4) enzyme, the major drug-metabolizing CYP isozyme in the human liver. We examined the enantioselective differences of KTZ in the inhibition of human CYP3A4 and in antifungal action. Dextro- and levo-KTZ exhibited modest enantioselective differences with respect to CYP3A4 inhibition of testosterone and methadone metabolism. For both substrates levo-KTZ was approximately a 2-fold more potent inhibitor. We examined the enantioselective differences in the in vitro activity of KTZ against medically relevant species of Candida and Aspergillus, as well as Cryptococcus neoformans. Overall, levo-KTZ was 2-4-fold more active than dextro-KTZ. Therefore, levo-KTZ is a more potent inhibitor of CYP3A4 and has stronger in vitro antifungal activity. Chirality 16:79-85, 2004.
Dilmaghanian
Shahrzad
S
Division of Clinical Pharmacology and Toxicology, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Gerber
John G
JG
Filler
Scott G
SG
Sanchez
Angela
A
Gal
Joseph
J
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D002175:Candida / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000737:chemistry* / Q000494:pharmacology*; D008691:Methadone / Q000378:metabolism*; D015394:Molecular Structure; D013237:Stereoisomerism; D013739:Testosterone / Q000378:metabolism*
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D008691:Methadone