Effect of ketoconazole on hepatic oxidative drug metabolism

Abstract

Several clinical reports have suggested (but not demonstrated) that ketoconazole, a broad-spectrum antifungal drug, may inhibit hepatic oxidative drug metabolism in man. We recently demonstrated that ketoconazole inhibits caffeine and aminopyrine oxidation in the rat; we now study the influence of ketoconazole on theophylline and chlordiazepoxide kinetics in man. These studies were performed before and after varying doses of ketoconazole within the currently accepted therapeutic range. Ketoconazole had no effect on theophylline clearance, whereas the drug impaired chlordiazepoxide clearance from plasma. After a single dose of ketoconazole, there was a 20% decrease in clearance and a 26% decrease in volume of distribution without evidence of inhibition of drug metabolism. These changes apparently were not related to ketoconazole dose. After repetitive dosing with ketoconazole, chlordiazepoxide clearance decreased by 38% and was associated with reduced concentrations of its first oxidative metabolite, N-desmethylchlordiazepoxide. We conclude that ketoconazole inhibits at least one subset of the hepatic mixed-function oxidase system, but is not as general an inhibitor of hepatic oxidative drug metabolism as cimetidine appears to be. For some coadministered drugs, ketoconazole may also have an effect on other kinetic parameters such as volume of distribution. Therefore, we caution that clinically important drug interactions may occur with the concurrent use of ketoconazole.

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

“…Many of the azole antimycotics, including ketoconazole, in addition to inhibiting fungal P-450, also inhibit hepatic oxidative enzymes. This is because these compounds have readily accessible non-bonded electrons on a nitrogen atom, the imidazole 3-N, enabling them to bind (Type II interaction) to the ferric form of the haemoprotein as a sixth ligand (Sheets & Mason, 1984;Back & Tjia, 1985;Meredith et al, 1985;Brown et al, 1985;Sheets et al, 1986;Lavrijson et al, 1987;. In contrast, terbinafine is a Type I substrate for a small portion of cytochrome(s) P-450 of hepatic microsomes (Schuster, 1987).…”

In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.

“…In addition, we have examined a number of imidazole and aminoquinoline derivatives. Many of these compounds have previously been shown to be inhibitors of oxidative enzymes (Back etal., 1983a,b;Murray, 1984;Thabrew & Ioannides, 1984;Sheets & Mason, 1984;Back & Tjia, 1985;Brown et al, 1985;Meredith et al, 1985;Mihaly et al, 1985;Riviere & Back, 1985, 1986Cockburn, 1986;Sheets et al, 1986;Lavrijsen et al, 1987).…”

Critical Ketoconazole Dosage Range for Ciclosporin Clearance Inhibition in the Dog

“…Therefore, careful monitoring of CsA blood levels is necessary and has helped to identify many important drug in teractions between CsA and other agents commonly used in the transplant recipient [7][8][9]Kétoconazole (KC), an imidazole-based antifungal agent, is a potent inhibitor of the hepatic cytochrome P-450 mixed function oxidase enzyme system responsible for the metabolism of CsA in vivo [10,11]. The interaction of KC with CsA in transplant recipients may result in extremely elevated CsA blood levels [12].…”