title: Effect of voriconazole and other azole antifungal agents on CYP3A activity and metabolism of tacrolimus in human liver microsomes.
abstract: Azole antifungal agents are known to inhibit cytochrome P450 3A (CYP3A) enzymes. Limited information is available regarding the effect of voriconazole on CYP3A activity. We examined the effect of voriconazole on CYP3A activity in human liver microsomes as measured by the formation of 6β-hydroxytestosterone from testosterone. We also evaluated the interaction between voriconazole and tacrolimus, an immunosuppressive drug, using human liver microsomes. The effect of voriconazole on CYP3A activity and tacrolimus metabolism was compared to that of other azole antifungal agents. CYP3A4 activity and the metabolism of tacrolimus were measured in the absence and in the presence of various concentrations of voriconazole (0-1.43 mM), fluconazole (0-1.63 mM), itraconazole (0-14 µM) and ketoconazole (0-0.19 µM). At a concentration of 21.2 ± 15.4 µM and 29.8 ± 12.3 µM, voriconazole inhibited the formation of 6β-hydroxytestosterone from testosterone and the metabolism of tacrolimus by 50%, respectively. The rank order of inhibition of 6β-hydroxytestosterone formation from testosterone and the metabolism of tacrolimus, is ketoconazole > itraconazole > voriconazole > fluconazole. Our observations suggest that voriconazole at clinically relevant concentrations will inhibit the hepatic metabolism of tacrolimus and increase the concentration of tacrolimus more than two-fold. Close monitoring of the blood concentrations and adjustment in the dose of tacrolimus are warranted when transplant patients receiving tacrolimus are treated with voriconazole.
authors: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Shimin
authors: S
authors: Zhang
authors: Venkateswaran C
authors: VC
authors: Pillai
authors: Sripal Reddy
authors: SR
authors: Mada
authors: Steve
authors: S
authors: Strom
authors: Raman
authors: R
authors: Venkataramanan
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity / Q000187:drug effects; D016559:Tacrolimus / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D013739:Testosterone; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole; D016559:Tacrolimus