Triazolam pharmacokinetics

Kinirons, M. T. el al. (1996). Triazolam pharmacokinetics and pharmacodynamics in Caucasians and Southern Asians ethnicity and CYP3A activity. Br. J. Clin. Pharmacol., 41, 69-72. 

Fahey JM, Pritchard GA, von Moltke LL, et al. The effects of ketoconazole on triazolam pharmacokinetics, pharmacodynamics and benzodiazepine receptor binding in mice. J Pharmacol Exp Ther 1998 285 271-276. 

Ochs HR, Greenblatt DJ, Burstein ES. Lack of influence of cigarette smoking on triazolam pharmacokinetics, BrJ Clin Pharmacol (1987) 23,759-63. 

Yuan R, Flockhart DA, Balian JD Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol 1999,39 1109-1125. 

Varhe, A., Olkkolam, K.T., and Neuvonen, P.J. (1994) Pharmacokinetics and drug disposion oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 56 601—607. 

Smith MA, Davidson J, Ritchie JG, et al The corticotropin-releasing hormone test in patients with post-traumatic stress order. Biol Psychiatry 26 349-355, 1989 Smith MA, Makino S, Kvetnansky R, et al Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15 1768-1777, 1995 Smith RB, Divoll M, Gillespie WR, et al Effect of subject age and gender on the pharmacokinetics of oral triazolam and temazepam. J Chn Psychopharmacol 3 172-176, 1983... 

A BZD s pharmacokinetics may play a role in the occurrence, in part accounting for the increase in its incidence after the advent of short-acting BZD anxiolytics and hypnotics (e.g., lorazepam, alprazolam, and triazolam). 

Warot D, Bergougnan L, Lamiable D, et al. Troleandomycin-triazolam interaction in healthy volunteers pharmacokinetic and psychometric evaluation. EurJ Clin Pharmacol 1987 32 389-393. 

Alprazolam did not exhibit any changes in pharmacokinetic parameters when administered concomitantly with GFJ (130) in a single dose experiment. When predosing existed, GFJ increased the exposure of alprazolam only in smokers. However, this interaction seems unlikely to be clinically relevant. In both parts of this study psychomotor fimction remained unchanged however, there was a small decrease in cognitive speed in the single dose part at one and two hours after dosing. Midazolam (6,15,133,134) and triazolam... 

Pharmacokinetics differ significantly among the most widely used benzodiazepine hypnotics, with some such as triazolam (Fig. 8—31) having rapid onset and short... 

The pharmacokinetics of saquinavir is modified by agents that alter isoenzyme CYP3A4 of the cytochrome P-450 system and P-glycoprotein transporter. It should not be administered with midazolam, triazolam and ergot derivatives. The plasma concentrations of saquinavir are lower when coadministered with efavirenz, nevirapine or rifampin. Ritonavir reverses the effects of nevirapine on saquinavir. The coadministration of astemizole, terfenadine, amiodarone, bepridil, quinidine, propafenone or flecainide with saquinavir is also not recommended due to its potential for serious and/or life-threatening reactions. 

Meanwhile, the currently marketed CYP3A4 inducers can profoundly affect the pharmacokinetics of coadministered CYP3A4 substrates, e.g., rifampin on midazolam (139) or triazolam (140). Clearly, the most frequent outcome is a loss of efficacy, which is perhaps less serious than inhibition interactions, although the consequences of coadministering rifampin with the oral contraceptive pill can lead to contraceptive failure (141-143). 

Phillips J, Antal E, Smith R. A pharmacokinetic drug interaction between erythromycin and triazolam. J Clin Psychopharmacol 1986 6 297-299. 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

Triazolam plasma concentrations were determined by gas chromatography with electron capture detection (73,95). The pharmacokinetic results demonstrated that mean clearance during Trials B and C were nearly identical (413 and 416 mL/min, respectively) that is, coadministration of azithromycin had no effect on the pharmacokinetics of triazolam (Fig. 5). However, triazolam clearance was significantly reduced to 146 mL/min by erythromycin (Trial D) and to 95 mL/min by clarithromycin (Trial E). Thus, the in vivo kinetic results are highly consistent with the in vitro data. 

Barbhaiya RH, Shukla UA, Kroboth PD, et al. Coadministration of nefazodone and benzodiazepines II. A pharmacokinetic interaction study with triazolam. J Clin Psychopharmacol 1995 15 320-326. 

Greenhlatt DJ, Harmatz JS, von Moltke LL, et al. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clin Pharmacol Ther 2004 76 467 479. 

In a double-blind, crossover, pharmacokinetic and pharmacodynamic study of the interaction of ketoconazole with alprazolam and triazolam, two CYP3A4 substrate drugs with different kinetic profiles, impaired clearance by ketoconazole had more profound clinical consequences for triazolam than for alprazolam (39). 

In a randomized, double-bhnd, pharmacokinetic-pharmacodynamic study, 12 volunteers took placebo or triazolam 0.125 mg orally, together with placebo, azithromycin, erythromycin, or clarithromycin. The apparent oral clearance of triazolam was significantly reduced by erythromycin and clarithromycin. The peak plasma concentration was correspondingly increased, and the half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced by erythromycin and clarithromycin (23). 

Similarly, itraconazole 200 mg did not alter the pharmacokinetics and pharmacodynamics of zolpidem 10 mg in 10 healthy volunteers (46). Therefore, unlike triazolam, zolpidem may be used in normal or nearly normal doses together with itraconazole. 

Despite common actions upon GABA, no pharmacodynamic or pharmacokinetic interations have been shown when tiagabine is combined with the benzodiazepine triazolam or with alcohol... 

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