The effects of the important antifungal agents, ketoconazole (Ket) and fluconazole (Flu), on the microsomal metabolism of cyclosporin A (CsA) by seven human livers was measured in vitro. A total of eight CsA metabolites were identified by high-performance liquid chromatography, with metabolites AM9 and AM1 predominating. Ket was a stronger inhibitor than Flu for the formation of each of the 8 metabolites; the mean IC50 for the inhibition of total CsA metabolism was 0.26 plusmn; 0.08 micro;M and 85.7 plusmn; 23.9 micro;M for Ket and Flu, respectively. Inhibition by Ket and Flu was noncompetitive, with Ki = 0.13 micro;M and 25.1 micro;M, respectively. There was considerable interindividual variation in the sensitivity of CsA metabolism to inhibition by Ket or Flu and the degree of inhibition was not uniform across the range of individual CsA metabolites. In six of the seven livers tested, Ket and Flu inhibited the aggregate formation of secondary metabolites (AM19, AM49, AM4N9, and AM1c) more than the aggregate formation of primary metabolites (AM9, AM1, and AM4N) and inhibited the formation of AM9 more than AM1. Although the degree of inhibition of total CsA metabolism by Flu correlated directly with the control (uninhibited) rate of total CsA metabolism (r= 0.95), no similar correlation for inhibition by Ket was noted, nor was the magnitude of inhibition by Ket and Flu related. The results are discussed in relation to the inhibition of CsA metabolism by Ket and Flu in patients in vivo and to the possibility of changes in the efficacy and toxicity of CsA as a result of alterations in its metabolite profile.
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