TY - JOUR
T1 - Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men
AU - Derry, C. L.
AU - Kroboth, P. D.
AU - Pittenger, A. L.
AU - Kroboth, F. J.
AU - Corey, S. E.
AU - Smith, R. B.
PY - 1995/6/13
Y1 - 1995/6/13
N2 - This study was designed to determine whether differences in α-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 α-1 acid glycoprotein concentrations between groups but no difference in free fraction of triazolam. There was a longer terminal half-life (t( 1/2 β)) 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. Thus, the AUEC, AUEC/f'AUC, EC50, and logistic regression results concur, suggesting similarity in response between normal weight and obese subjects after the first exposure to triazolam and a greater response after the second exposure, particularly in the obese.
AB - This study was designed to determine whether differences in α-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 α-1 acid glycoprotein concentrations between groups but no difference in free fraction of triazolam. There was a longer terminal half-life (t( 1/2 β)) 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. Thus, the AUEC, AUEC/f'AUC, EC50, and logistic regression results concur, suggesting similarity in response between normal weight and obese subjects after the first exposure to triazolam and a greater response after the second exposure, particularly in the obese.
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U2 - 10.1097/00004714-199506000-00008
DO - 10.1097/00004714-199506000-00008
M3 - Article
C2 - 7635997
AN - SCOPUS:0029079408
SN - 0271-0749
VL - 15
SP - 197
EP - 205
JO - Journal of Clinical Psychopharmacology
JF - Journal of Clinical Psychopharmacology
IS - 3
ER -