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Azoles, a48 llylamines and drug metabolism
Author(s) -
BACK D.J.,
TJIA J.F.,
ABEL S.M.
Publication year - 1992
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/j.1365-2133.1992.tb00003.x
Subject(s) - ketoconazole , itraconazole , terbinafine , fluconazole , pharmacology , drug interaction , chemistry , allylamine , drug metabolism , azole , pharmacokinetics , medicine , drug , antifungal , dermatology , polyelectrolyte , organic chemistry , polymer
Summary Four antifungal drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine, were studied for their effects on the metabolism of cyclosporine A (CyA) and cortisol by human liver microsomes in vitro ( n =3). Ketoconazole produced marked inhibition of CyA hydroxylase (to metabolites M17 and M1) with IC 50 and K i values of 0.24±0.01 and 0.022±0.004 μ m , respectively. On the basis of the IC 50 , itraconazole was 10 times less potent (IC 50 of 2.2±0.2 μ m ), and fluconazole and terbinafine were each above 100 μ m . No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Ketoconazole was the most potent inhibitor of cortisol metabolism (to 6 β ‐hydroxycortisol, IC 50 =0.6 μ m ). Itraconazole produced marked inhibition of cortisol metabolism (IC 50 =2.4 μ m ), but fluconazole and terbinafine had little effect. These data confirm that ketoconazole is a potent inhibitor of cytochrome P‐450‐IIIA4, and this has clinical relevance. Although the inhibition with fluconazole was much less than with itraconazole at equimolar concentrations, it should be noted that in‐vivo plasma concentrations of fluconazole are much greater than that of itraconazole. Clinical interactions of CyA with both fluconazole and intraconazole have been reported; in contrast to these azoles, terbinafine does not have the same interaction potential.