Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro.

Abstract

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine, have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes (n = 4) in vitro.

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

“…In vitro terbinafine did not inhibit cyclosporin metabolism, confirming the results of a previous study (Back et al, 1989). The novel structure of terbinafine precludes binding to known cytochrome P450 isoenzymes.…”

“…Cyclosporin hydroxylase activity was determined as described previously (Back et al, 1989), with the following modifications: Incubations contained cyclosporin (CsA; 5 JIM, [3H]-CsA; 0.1 ,uCi, a gift from Sandoz Pharmaceuticals, Basle), and microsomal protein (1.5 mg) and were performed in 10 ml wide neck glass tubes at 370 C with agitation for 20 min. Other reaction constituents and the extraction procedure remained unchanged.…”

“…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).…”

Update on terbinafine with a focus on dermatophytoses

“…69 For drugs that are not substrates of CYP2D6 (eg, anticoagulants, corticosteroids, oral contraceptives, tolbutamide, cyclosporine, midazolam, digoxin and terfenadine) terbinafi ne has only a modest or minimal affect on their metabolism. [70][71][72][73][74] However, as a substrate of the cytochromes P450, the pharmacokinetics of terbinafi ne are altered with the concurrent administration of several agents (eg, cimetidine, terfenadine, rifampin). 70,75 The clearance of terbinafi ne is triphasic with the terminal elimination half-life approximating 100 hours after a single dose and 22 days with durations of therapy spanning several months.…”

Venlafaxine oxidation in vitro is catalysed by CYP2D6

“…P450 substrate/inhibitors were examined at concentrations reported to cause preferential inhibition of the isoform: phenacetin for CYPlA2 [23]; diethyldithiocarbamate for CYP2E1 [24]; tolbutamide for CYPZC8/9 [25]; troleandomycin [26] for CYP3A3/4. Ketoconazole was also used to inhibit CYP3A4 [27,281. Although inhibition by diethyldithiocarbamate has been taken as evidence for the involvement of CYP2E1 [24], a recent study showed that it is not selective for this isoform; at the concentrations used here, it also inhibits CYP2B6 and CYP2A6 [29].…”