title: 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)
authors.affiliation: University of Pittsburgh Pharmacodynamic Research Center, PA 15261, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Derry
authors.forename: P D
authors.initials: PD
authors.lastname: Kroboth
authors.forename: A L
authors.initials: AL
authors.lastname: Pittenger
authors.forename: F J
authors.initials: FJ
authors.lastname: Kroboth
authors.forename: S E
authors.initials: SE
authors.lastname: Corey
authors.forename: R B
authors.initials: RB
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000523:psychology; D011581:Psychological Tests; D011597:Psychomotor Performance / Q000187:drug effects*; D014229:Triazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D014229:Triazolam