Effect of fluconazole dose on the extent of fluconazole-triazolam interaction

Abstract

1 Azole antimycotics interact with the short acting hypnotic triazolam. The effect of fluconazole dose on the extent of fluconazole-triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases. 2 Eight healthy volunteers received either 50 mg, 100 mg or 200 mg (400 mg on day 1) of fluconazole or placebo orally once a day for 4 days. On day 4, they took a 0.25 mg oral dose of triazolam, after which plasma samples were collected and pharmacodynamic effects measured for 18 h.

Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

“…The minor effect of itraconazole on oxycodone-induced pharmacological response despite the clear changes in its pharmacokinetics is well in line with the log-linear relationship between drug concentration and effect and the relatively small dose of oxycodone used in our study [31,32]. Azole antimycotics are known to have significant interactions with several substrates of CYP3A [15,16,[33][34][35]. With respect to other substrates of CYP3A, itraconazole has been found to decrease the mean plasma Cl of intravenous midazolam by 69% and increase the AUC (0-∞) of oral midazolam by 660% [14].…”

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

“…The extent of inhibition or induction of drug metabolizing enzyme activity is often concentration dependent (182). Therefore, a constant concentration of the inhibitor/inducer is customarily maintained studies performed in vitro.…”

Fluconazole but not the CYP3A4 inhibitor, itraconazole, increases zafirlukast plasma concentrations

“…In vivo, the inhibitory effect of fluconazole on CYP3A4-mediated metabolism is dose dependent. For example, 100 mg fluconazole daily has increased triazolam AUC only 2.1-fold, whereas the same dose of fluconazole as used in the study presented here (200 mg daily), has produced a 4.4-fold increase in triazolam AUC [34]. Furthermore, fluconazole (400 mg daily) has inhibited in vivo CYP2C9 catalyzed hydroxylations of S-warfarin by about 70% and the CYP3A4-mediated 10-hydroxylation of R-warfarin by 45%, with a resultant 3-and 2-fold increase, respectively in S-and R-warfarin AUCs [35].…”