Titre du document / Document title

Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men

Auteur(s) / Author(s)

OLUBODUN Joel O. ⁽¹⁾ ; OCHS Hermann R. ⁽²⁾ ; VON MOLTKE Lisa L. ⁽¹⁾ ; ROUBENOFF Ronenn ⁽¹⁾ ; HESSE Leah M. ⁽¹⁾ ; HARMATZ Jerold S. ⁽¹⁾ ; SHADER Richard I. ⁽¹⁾ ; GREENBLATT David J. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Pharmacology and Experimental Therapeutics and the Jean Mayer USDA Human Nutrition Research Center on Ageing, Tufts University School of Medicine and Tufts-New England Medical Center, Boston, MA, ETATS-UNIS
⁽²⁾ Marien-Krankenhaus, Soest, ALLEMAGNE

Résumé / Abstract

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), C_max 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), C_max increased (108 vs 60 ng ml^-1, P < 0.001), with no difference in t_v, (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 μM) 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 μM). However, testosterone did not induce immunoactive CYP3A4 expression or catalytic function in cultured human hepatocytes. Conclusions The increased C_max 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.

Revue / Journal Title

British journal of clinical pharmacology   ISSN 0306-5251   CODEN BCPHBM 

Source / Source

2003, vol. 56, n^o3, pp. 297-304 [8 page(s) (article)] (54 ref.)

Langue / Language

Anglais

Editeur / Publisher

Blackwell Science, London, ROYAUME-UNI  (1974) (Revue)

Mots-clés anglais / English Keywords

Androgen ; Gabaergic agonist ; Gabaergic receptor A ; Agonist ; Sedative ; Hypnotic ; Human ; Healthy subject ; Oral administration ; Metabolism ; In vitro ; In vivo ; Male ; Sex ; Age ; Young adult ; Elderly ; Pharmacokinetics ; Sex steroid hormone ; Testosterone ; Zolpidem ;

Mots-clés français / French Keywords

Androgène ; Stimulant gabaergique ; Récepteur gabaergique A ; Agoniste ; Sédatif ; Hypnotique ; Homme ; Imidazo pyridine dérivé ; Individu sain ; Voie orale ; Métabolisme ; In vitro ; In vivo ; Mâle ; Sexe ; Age ; Adulte jeune ; Personne âgée ; Pharmacocinétique ; Hormone stéroïde sexuelle ; Testostérone ; Zolpidem ;

Mots-clés espagnols / Spanish Keywords

Andrógeno ; Estimulante gabaérgico ; Receptor gabaminérgico A ; Agonista ; Sedante ; Hipnótico ; Hombre ; Individuo sano ; Vía oral ; Metabolismo ; In vitro ; In vivo ; Macho ; Sexo ; Edad ; Adulto joven ; Anciano ; Farmacocinética ; Hormona esteroide sexual ; Testosterona ; Zolpidem ;

Mots-clés d'auteur / Author Keywords

ageing ; pharmacokinetics ; testosterone ; zolpidem ;

Localisation / Location

INIST-CNRS, Cote INIST : 16791, 35400011432821.0070