Pharmacokinetics and Pharmacodynamics of Triazolam After Two Intermittent Doses in Obese and Normal-Weight Men

Abstract

This study was designed to determine whether differences in alpha-1 acid glycoprotein and free drug concentrations result in an altered response to triazolam. Twelve normal-weight and 12 obese adult male subjects received intravenous doses of triazolam, 0.5 mg, on two occasions separated by 1 week. There was a small difference in the alpha-1 acid glycoprotein concentrations between groups but no difference in free fraction of triazolam. There was a longer terminal half-life (t1/2 beta) in the obese subjects (3.16 +/- 0.87 vs. 3.83 +/- 1.24, p = 0.0098). Overall, week 1 data revealed no difference in effect between normal and obese subjects. However, response data reveal a pattern of increased sensitivity with the second exposure to triazolam. For example, area under the effect curve (AUEC) on all tests was significantly greater in week 2 for both groups of subjects. For a memory test and sedation from 0 to 12 hours, AUEC/free AUC ratios were significantly greater in week 2 for all subjects. The obese had a higher ratio on week 2 than on week 1 for all psychomotor tests and sedation (0 to 4.5 hours; p < 0.05). The results of modeling psychomotor impairment-concentration data pooled by group for each week continue the pattern: week 1 data are similar between the obese and normal-weight subjects. Although EC50 values are up to 15% lower in week 2 for the normal-weight subjects, EC50 values are as much as 66% lower in week 2 for the obese, where a lower EC50 indicates greater sensitivity. Logistic regression of the recognition data is consistent with these results.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered Drug Metabolism and Transport in Pathophysiological Conditions

“…Animal studies performed using a diabetes mellitus rat model (induced by alloxan or streptozotocin treatment) have reported altered PK of drugs such as acetaminophen, chlorzoxazone, theophylline, clarithromycin, furosemide, and methotrexate (Baek et al, 2006;Kim et al, 2005aKim et al, , 2005bPark et al, 1996Park et al, , 1998Watkins & Sherman, 1992). Although, no changes in PD of atracurium were reported in obese animals compared to lean control (Varin et al, 1990), triazolaminduced sedation in obese humans increased significantly compared to normal weight men (Derry et al, 1995). We also observed similar disparities in the PD of midazolam, CYP3A substrate, (increased sleep time) and zoxazolamine, CYP2E1 substrate (no change) in DIO mice (Ghose et al, 2011b).…”

Pharmacokinetic Considerations in Obesity

“…Cheymol et al 45 showed no significant differences in AAG between obese and lean individuals; however, a decrease in volume of distribution of propanolol was observed which was more consistent with increased plasma protein binding. Derry et al 46 also observed an increase in AAG with no change in the plasma free fraction of triazolam, a drug principally bound by AAG.…”

“…Obese subjects were shown to have increased sensitivity to triazolam as measured by a sedation score upon administration of a second dose. 46 The same dose of triazolam was used for both obese and nonobese individuals. Varin et al 41 showed that even though obese individuals were exposed to significantly higher plasma concentrations of atracurium, no change was seen in the duration of neuromuscular blockade.…”

Anesthesia in the obese patient: Pharmacokinetic considerations

“…It has been reported that the increased concentrations of triglycerides, lipoproteins, cholesterol, and free-fatty acids may inhibit protein binding of some drugs, increasing their free plasma concentrations [23]. On the other hand, the increase in concentrations of acute phase proteins, including a 1 -acid glycoprotein, observed in the obese patient may also increase the degree of binding of other drugs, reducing their free-plasma concentrations [24,25].…”