Troleandomycin-triazolam interaction in healthy volunteers: Pharmacokinetic and psychometric evaluation

Abstract

Seven healthy volunteers received a single oral dose of triazolam 0.25 mg after 7 days on troleandomycin 2 g/day p.o. or placebo in a double-blind cross-over study. Plasma triazolam and psychometric and memory tests (including Critical Flicker Fusion threshold, Choice Reaction Time, Digit Symbol Substitution and Self-Rating Scales) were assessed at regular intervals after the final treatment. Troleandomycin was found to prolong the psychomotor impairment and amnesia produced by triazolam. There was a significant enhancement of the AUC, the peak concentration and the delay to tmax of triazolam after 7 days treatment with troleandomycin compared to placebo. Thus, there is a pharmacokinetic interaction, and the combination of triazolam and troleandomycin should be avoided or the dose of triazolam should be adjusted. The most likely mechanism is a diminished hepatic first-pass effect, and a decrease in the apparent oral clearance of triazolam.

Oral Single Doses of Erythromycin and Roxithromycin May Increase the Effects of Midazolam on Human Performance

“…The combined effect of triazolam and erythromycin was milder than expected although a combination of triazolam 0.25 mg and troleandomycin 2 glday has prolonged the psychomotor impairment over that caused by triazolam alone (Warot et al 1987). It may be that the dose,of triazolam 0.25 mg (probably less potent than 15 mg midazolam) and the single 750 mg dose of erythromycin together offer an interaction that could not be reliably measured in our experimental set-up.…”

“…There have been controversial results with erythromycin concerning the affinity of the drug for cytochrome P450 binding sites and interactions with other drugs; it has been suggested that erythromycin base, also used in our design, has strong affinity for cytochrome P450 whereas erythromycin stearate does not bind very tightly to the enzyme (Descotes et al 1985). Macrolide antibiotics given in combination with drugs with extensive metabolic inactivation by the same or closely similar cytochrome P450 isoenzyme, inhibit their metabolism and thus lead to increased plasma levels and prolonged half-lives of these drugs, and ultimately to their enhanced effects as shown with triazolam (Phillips et al 1986;Warot et al 1987) and midazolam (Gascon & Drayer 1991;Olkkola et al 1993). Concentrations of erythromycin in liver and bile are large, and the drug binds to cytochrome P450 IIIA before Ndemethylation.…”

“…The ultrashort acting 1 ,Cbenzodiazepine hypnotics triazolam and midazolam are extensively metabolized in the liver by cytochrome P450 IIIA (Kronbach et al 1989;Gascon & Drayer 1991). Inhibition of their hepatic metabolism leads to increased plasma concentrations and enhanced effects of the drugs concerned, as shown for triazolam with erythromycin or troleandomycin (Phillips et al 1986;Warot et al 1987) and for midazolam with erythromycin given orally for one week (Olkkola et al 1993) or as a bolus intravenous injection (Hiller et al 1990). The present pharmacodynamic human study was conducted to find out if oral single doses of erythromycin and roxithromycin might enhance the sedative effects of single hypnotic doses of triazolam and midazolam.…”

Inhibition of triazolam clearance by macrolide antimicrobial agents: In vitro correlates and dynamic consequences*

“…However, a previous study showed a nearly 4-fold reduction in triazolam clearance caused by coadministration of troleandomycin. 6 Under some circumstances in vitro data on competitive inhibition of drug metabolism have been used for prospective quantitative estimation of pharmacokinetic drug interactions in vivo.l*,t4-16.24-27 However, impairment of cytochrome activity by macrolides is mechanism-based rather than competitive,s+t and a model for quantitative scaling of in vitro inhibition data has not been established. Our in vitro data nonetheless allowed prospective estimation that coadministration of azithromycin is unlikely to impair triazolam clearance, whereas impaired clearance by erythromycin or clarithromycin appears possible or probable.…”

Quantitative Correlations Among CYP3A Sensitive Substrates and Inhibitors:Literature Analysis

“…Indeed, we tested the assumption of substrate independence using a large pool of inhibition studies and found an appreciable number of exceptions. For example, inhibitors found to be potent with midazolam were classified as moderate with other sensitive substrates: ketoconazole (400 mg/day) and clarithromycin (1000 mg/day) exhibited AUC ratios of 2.9 [8], and 2.8 [9], respectively with saquinavir; two other potent inhibitors, troleandomycin (2 g/day) and nefazodone (400 mg/day) produced AUC ratios of 3.8 and 3.9, respectively with triazolam [10,11]. Similarly, moderate inhibitors (with midazolam) were found to behave as potent or weak inhibitors depending on the substrate.…”