Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men
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AIMS: The influence of ageing on the pharmacokinetics of zolpidem, an extensively prescribed hypnotic medication, was evaluated in healthy human volunteers. METHODS: A series of 16 elderly (age: 61-85 years) and 24 young (age: 22-42 years) volunteers received single 5 mg oral doses of zolpidem tartrate. Serum zolpidem concentrations were determined by HPLC with fluorescence detection in samples drawn during 8 h after dosage. The effect of testosterone on zolpidem biotransformation was evaluated in vitro using human liver microsomes. Possible induction of CYP3A protein expression and function was studied in cultured human hepatocytes. RESULTS: Among men, apparent oral clearance of zolpidem was decreased in elderly compared to young subjects (3.8 vs 11.0 ml min-1 kg-1, P < 0.01), Cmax was increased (93 vs 40 ng ml-1, P < 0.01), and half-life increased (2.7 vs 1.5 h, P < 0.03). Among women, zolpidem oral clearance was decreased in the elderly (3.0 vs 5.8 ml min-1 kg-1, P < 0.02), Cmax increased (108 vs 60 ng ml-1, P < 0.001), with no difference in t1/2 (2.3 vs 2.4 h). Among male subjects, free serum testosterone concentrations were lower in the elderly (10.5 vs 19.0 pg ml-1, P < 0.01), and were significantly correlated with zolpidem clearance (r2 = 0.46, P < 0.001). Multiple regression analysis indicated a greater relative contribution of serum testosterone than age to the oral clearance of zolpidem among men. In human liver microsomes, co-incubation of zolpidem (10 micro m) with varying concentrations of testosterone produced activation of biotransformation of zolpidem to its principal hydroxylated metabolite. Maximum activation was achieved at equimolar concentrations of testosterone (10 micro m). However, testosterone did not induce immunoactive CYP3A4 expression or catalytic function in cultured human hepatocytes. CONCLUSIONS: The increased Cmax and lower oral clearance of zolpidem in the elderly are consistent with recommendations of lower clinical doses of zolpidem in the elderly. Our clinical and in vitro data both suggest that reduced free serum testosterone may have a modulatory role in age-dependent changes in zolpidem pharmacokinetics in men.
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The US Food and Drug Administration revised zolpidem dosing recommendations in 2013, halving the prescribed doses for women.
“Reflecting these concerns, the US Food and Drug Administration (FDA) revised zolpidem dosing recommendations in 2013, halving the prescribed doses for women.”
From Z-drug abuse and dependence: Clinical guideline of the Brazilian Academy of Neurology for diagnosis and management (2025) · cites this paper as [46]
The Discussion (page not provided) recommends a lower zolpidem dose for elderly patients based on reduced clearance. A search for the FDA, 2013, and a halved dose for women found no passage addressing the claimed regulatory change; this 2003 paper does not verify it. (LLM, conf=0.78)
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- Authors
- Olubodun, J. O., Ochs, H. R., Von Moltke, L. L., Roubenoff, R., Hesse, L. M., Harmatz, J. S., Shader, R. I., & Greenblatt, D. J.
- Affiliations
- Tufts University (US)
- Corresponding author
- Greenblatt, David J.
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2003-07-22
- Volume
- 56
- Issue
- 3
- Pages
- 297-304
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC1884349
- OpenAlex
- W2169843481
- Cited by
- 104
- References
- 60
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 2 · 2019: 9 · 2018: 1 · 2017: 3 · 2016: 8 · 2015: 4 · 2014: 12 · 2013: 6 · 2012: 4
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-17880, R01AG017880)
- National Institute of Mental Health (MH 02137, MH 58435, R01MH058435)
- National Institute on Drug Abuse (R21DA013209, R01DA005258, DA 13209, DA05258)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK/AI 58496, R01DK058496)
- National Center for Research Resources (RR00054, M01RR000054)
- 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
- zolpidem, pharmacokinetics, aging, older adults, testosterone, CYP3A4, drug metabolism, oral clearance, Cmax, half-life, hypnotics, liver microsomes, CYP3A4 induction, sex differences, drug interactions, drug safety in older adults
- MeSH terms
- Zolpidem, Administration, Oral, Adult, Aged, Aged, 80 and over, Aging, Chromatography, High Pressure Liquid, Drug Interactions, Female, Half-Life, Humans, Hypnotics and Sedatives, Male, Microsomes, Liver, Middle Aged, Pyridines, Testosterone, GABA Agonists, Hepatocytes
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