Ketoconazole, Cyclosporin Metabolism, and Renal Transplantation

Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.

“…Sustained changes in cyclosporin concentration can result in graft rejection or renal toxicity (Yee & McGuire, 1990). The present in vitro study confirms that ketoconazole is a potent inhibitor of CsA metabolism and, thereby, will cause plasma CsA concentrations to increase when coadministered (Dieperink & Moller, 1982;Ferguson et al, 1982;Cockburn, 1986). It has been suggested that the co-administration of ketoconazole could reduce CsA dosage requirements with consequent cost implications (First et al, 1989(First et al, , 1991, although this has been challenged (Frey, 1990).…”

“…Ketoconazole is a potent inhibitor of cyclosporin metabolism by human liver microsomes in vitro (Back et al, 1989;Burke et al, 1990) and it is this inhibition that gives a rational basis to the clinically important interactions reported in transplant patients (Cockburn, 1986;Dieperink & Moller, 1982;Ferguson et al, 1982). Fluconazole administration has also been shown to alter cyclosporin pharmacokinetics (Graves et al, 1990;Lazar & Wilner, 1990;Sugar etal., 1989).…”

Overview of medically important antifungal azole derivatives

“…Serum levels of ketoconazole also are decreased by concomitant administration of rifampin, apparently due to accelerated hepatic metabolism (35). Adverse interaction of ketoconazole and cyclosporin is well described, leading to elevated toxic levels of cyclosporin (70,85,271,276 (192). Sobel (277) demonstrated that oral ketoconazole was effective in the prophylactic treatment of recurrent vaginal candidiasis, but he cautioned that the incidence of hepatic injury by the drug must be considered in treating patients with this syndrome.…”

Interaction between cyclosporin A and phenobarbitone [letter]

“…Drugs known to be inhibitors of this enzyme system, e.g. ketoconazole (Ferguson et al, 1982) and cimetidine , increase CSA serum levels, while rifampicin (Langhof & Madsen, 1983) and phenytoin (Freeman et al, 1984), both known to activate hepatic microsomal cytochrome P-450 (Herman et al, 1983;Pirttiaho et al, 1982), have been reported to reduce serum levels of CSA in humans. We suggest that such an interaction was responsible for the enhancement of elimination of CSA observed in the following case, in which phenobarbitone was given simultaneously, and which to our knowledge only has been reported briefly in the previous literature (Burckart et al, 1984;Wideman, 1983).…”