Abstract
This study was designed to determine whether age influences sensitivity to alprazolam and/or rate of acute tolerance development to the effects of alprazolam. Three treatments were each separated by 4 weeks. Twenty-five young (ages 22- 35) and 13 elderly (ages 65–75) men received 2 mg of alprazolam/2 min i.v. Blood samples were obtained over 48 hr, and sedative, psychomotor and memory effects were assessed serially for 12 hr. Clearance was lower (P = .05) and eliminationt [1/2] was longer (P = .005) in the elderly, but area under the concentration curve to 12 hr and maximum concentration did not differ by age group. Maximum impairment was greater in the elderly for all assessments. Mean EC50values differed between the elderly (25.3 and 25.0 ng/ml) and the young (39.8 and 36.5 ng/ml) on card sorting and digit symbol substitution, respectively (P < .001). Bolus treatment data were used to individualize doses for the crossover of placebo and alprazolam; infusions were designed to maintain a plateau alprazolam concentration between 1 and 9 hr. Alprazolam concentrations through 12 hr did not differ between the young and elderly. Mediant [1/2] for offset of effect for digit symbol substitution was 2.8 hr in the young and 4.9 hr in the elderly (P = .05). Therefore, aging decreases alprazolam clearance and increases sensitivity to effects of alprazolam through a mechanism other than pharmacokinetics; aging also decreases the rate of offset of effect of alprazolam. In addition, the data provide insight into the intensity of initial effect as a determinant of rate of tolerance development.
Footnotes
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Send reprint requests to: Patricia D. Kroboth, Ph.D., University of Pittsburgh/Pharmacodynamic Research Center, 904 Salk Hall, Pittsburgh, PA 15261
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↵1 This research was sponsored by The Upjohn Company and by NIH/NCRR/GCRC Grant 5-M01-RR00056 and was presented in two parts at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meetings in March 1994 and March 1995.
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↵2 Fellow of the American Foundation for Pharmaceutical Education. Present address: Abbott Laboratories, Research Pharmacokineticist, Department of Pharmacokinetics and Biopharmaceutics.
- Abbreviations:
- AUC
- area under the plasma concentration curve
- AUEC
- area under the effect curve
- CS
- card sorting task
- CPT
- continuous performance test
- DSST
- digit symbol substitution test
- EC50
- concentration that elicits half-maximal response
- Eo
- baseline
- kt
- tolerance rate constant or effect offset rate constant
- MaxOE
- maximum observed effect
- Mn1–9hr
- mean alprazolam concentration from 1 to 9 hr
- MnE1–9hr
- mean effect from 1 to 9 hr
- NRSS
- nurse-rated sedation score
- RMT
- Randt Memory Test
- tMaxOE
- time to maximum effect
- t[1/2]β
- half-life for elimination of drug
- t[1/2]t
- half-life for offset of effect
- Received July 11, 1996.
- Accepted February 5, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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