Background Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with triazolam in humans is important to uncover. Methods In this double‐blind, randomized, three‐phase crossover study, the interaction between ketoconazole, itraconazole, and triazolam was investigated. Nine healthy young volunteers received either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo (control phase) orally once a day for 4 days. On day 4, each ingested a single 0.25 mg dose of triazolam. Plasma concentrations of triazolam and antimycotics were determined, and pharmacodynamic effects were measured up to 17 hours. Results On average, ketoconazole and itraconazole increased the area under the triazolam concentration–time curve [AUC(0‐∞)] 22‐fold and 27‐fold (p < 0.001), the peak concentrations threefold (p < 0.001), and the elimination half‐life sixfold and sevenfold (p <0.001), respectively. In seven of the nine subjects, even the maximum concentration of triazolam in plasma was lower without the antimycotics than were the 17‐hour concentrations during the ketoconazole and itraconazole phases. All pharmacodynamic effects (e.g., the Digit Symbol Substitution Test) revealed a significant difference between the antimycotic and placebo phases. Conclusions Both ketoconazole and itraconazole seriously affect the pharmacokinetics of triazolam and increase the intensity and duration of its effects. Inhibition of CYP3A4 during the absorption and elimination phases of triazolam seems to explain the interaction observed. Because of the potentially hazardous consequences of this interaction, triazolam should be avoided if patients are using ketoconazole or itraconazole. Clinical Pharmacology and Therapeutics (1994) 56, 601–607; doi:

Background Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A enzymes. Ketoconazole and itraconazole can increase the area under the concentration‐time curve [AUC(0‐∞)] of triazolam, a substrate of CYP3A, by more than twenty times. Methods In this randomized crossover study the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of triazolam was investigated. Ten healthy young subjects received a single 0.25 mg dose of triazolam with either 250 ml grapefruit juice or water. Plasma concentrations and effects of triazolam were measured up to 17 hours. Results Grapefruit juice increased the AUC(0‐∞) of triazolam in each subject and the peak concentration in nine of the 10 subjects. The mean AUC(0‐∞) of triazolam was increased 1.5‐fold (p < 0.001) and the peak concentration was increased 1.3‐fold (p < 0.05) by grapefruit juice. Grapefruit juice postponed the peak time of triazolam from 1.6 hours to 2.5 hours (p < 0.05). Grapefruit juice increased the effects of triazolam slightly; drowsiness was significantly (p < 0.05) enhanced. Conclusions Grapefruit juice can increase the plasma concentrations and effects of oral triazolam. Clinical Pharmacology & Therapeutics (1995) 58, 127–131; doi:

Aims Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral L -dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of L -dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of L -dopa given as standard release L -dopa/carbidopa. Methods Six different doses of L -dopa/carbidopa were investigated in this placebocontrolled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups ( n = 14-16). Two different L -dopa/carbidopa doses were administered to each subject (50/ 12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/ 25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of L -dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(0,12 h) of L -dopa to a similar extent at all doses of L -dopa/carbidopa, that is by about 30-40% compared with placebo ( P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C max values for L -dopa at all L -dopa/ carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of L -dopa were maintained for a longer period at all doses of L -dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-Omethyldopa (3-OMD) to about 55-60% of the placebo treatment level ( P < 0.001, 95% CI -0.72, -0.35) and increased the mean AUC(0,12 h) of 3,4-dihydroxyphenylacetic acid (DOPAC) 2-2.6-fold compared with placebo ( P < 0.001, 95% CI 0.60, 1.10). The mean AUC(0,12 h) of 3-methoxy-4-hydroxy-phenylacetic acid (HVA) following entacapone was approximately 65-75% of that observed with placebo ( P < 0.001-0.05, 95% CI -0.76, -0.01) at each L -dopa/carbidopa dose except the 50/12.5 mg dose ( P > 0.05, 95% CI -0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC L -dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD ( P < 0.001, 95% CI -0.85, -0.68) and HVA ( P < 0.001, 95% CI -1.01, -0.18) in plasma at each L -dopa/carbidopa dose, whereas the AUC DOPAC/AUC L -dopa ratio was increased again at all doses ( P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did L -dopa/carbidopa affect the pharmacokinetics of entacapone.H. Heikkinen et al. 364

Even a single 200 mg dose of itraconazole interacts considerably with triazolam when this hypnotic agent is ingested within 24 hours after itraconazole. Thus during the daily itraconazole use this interaction cannot be avoided by increasing the time interval between their intake. Furthermore, the risk of interaction is obvious for several days after the cessation of itraconazole therapy.

Diltiazem has a clinically significant interaction with oral triazolam. The data is highly suggestive that diltiazem inhibits the metabolism of triazolam during the first-pass and elimination phases. Prescription of triazolam should be avoided if a patient is using diltiazem or other potent inhibitors of CYP3A.