Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate
Abstract
Sixty-one healthy men and women, aged 20 to 75 years, received single 0.25-mg doses of triazolam, a cytochrome P450 (CYP) 3A substrate benzodiazepine, and placebo in a double-blind crossover study. Among women, age had no significant effect on area under the triazolam plasma concentration curve (AUC) (Spearman r=0.14, P=.44) or clearance (r =-0.09, P=.62). Among men, AUC increased (r=0.43, P <.02) and clearance declined (r=-0.42, P <.02) with increasing age. Gender differences in triazolam kinetics were not apparent. Compared with placebo, triazolam impaired digit-symbol substitution test performance, increased observer-rated sedation, impaired delayed recall of information learned at 1.5 hours after dosing, and increased electroencephalographic beta amplitude. Among men, mean values of relative digit-symbol substitution test decrement (P <.002) and observer-rated sedation (P <.05) were significantly greater in elderly subjects compared with young subjects. Age-dependent differences among women reached significance for observer-rated sedation (P <.02). A combination of higher plasma levels and increased intrinsic sensitivity explained the greater pharmacodynamic effects of triazolam in elderly subjects. Although the findings are consistent with reduced clearance of triazolam in elderly men, individual variability was large and was not explained by identifiable demographic or environmental factors.
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The percent decrement in DSST scores with age was significantly greater in men than in women.
“The percent decrement in DSST scores with age was also significantly greater in men than in women.”
From Digit Symbol Substitution Test: The Case for Sensitivity Over Specificity in Neuropsychological Testing (2018) · cites this paper as [35]
In a double-blind crossover study, there was a statistically significant effect of age on predose DSST performance, with lower baseline scores in elderly subjects.
“This double-blind crossover study demonstrated a statistically significant effect of age on predose DSST performance, with lower baseline scores in the elderly subjects further reinforcing the effect of age on DSST performance.”
From Digit Symbol Substitution Test: The Case for Sensitivity Over Specificity in Neuropsychological Testing (2018) · cites this paper as [35]
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- Authors
- GREENBLATT, D., HARMATZ, J., VONMOLTKE, L., WRIGHT, C., & SHADER, R.
- Affiliations
- Tufts University (US)
- Corresponding author
- GREENBLATT, D
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2004-11
- Volume
- 76
- Issue
- 5
- Pages
- 467-479
- ISSN
- 0009-9236 (ISSN-L)
- OpenAlex
- W2125237026
- Cited by
- 93
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 4 · 2013: 7 · 2012: 8
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-17880, R01AG017880)
- National Institute of Mental Health (MH 58435, R01MH058435)
- National Institute on Drug Abuse (DA 13834, R21DA013209, R01DA013834, DA 13209, DA05258)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-58435)
- National Center for Research Resources (RR00054, M01RR000054)
- National Center for Complementary and Integrative Health (R01AT001381, AT01381)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Keywords
- triazolam, age effects, gender differences, pharmacokinetics, pharmacodynamics, CYP3A, benzodiazepines, older adults, drug clearance, sedation, cognitive impairment, Digit Symbol Substitution Test, interindividual variability
- MeSH terms
- Adult, Aged, Aging, Aryl Hydrocarbon Hydroxylases, Double-Blind Method, Electroencephalography, Female, Half-Life, Humans, Hypnotics and Sedatives, Male, Middle Aged, Oxidoreductases, N-Demethylating, Mental Recall, Sex Characteristics, Triazolam, Cross-Over Studies, GABA Modulators, Area Under Curve, Cytochrome P-450 CYP3A
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