Summary of Studies Showing Sex-Differences in Pharmacokinetics:
Psychoactive Medications
Many anticholinergic psychoactive medications have been investigated for
sex-differences in absorption, distribution, metabolism and excretion. A
study of cyclobenzaprine examined sex-differences using a series of
open-label, three-period, randomized, crossover studies. The first study
included 24 healthy young subjects (mean age: 25.5 years), the second 18
healthy subjects (mean age: 28.7 years), and the third 12 older subjects
(mean age: 71.3 years). The primary objective was to investigate the
pharmacokinetics and bioavailability of cyclobenzaprine with attention
to the effects of sex, age and hepatic insufficiency (table 2). There
were small significant differences in the area under the curve (AUC) and
CMAX between sexes in the older
group77. This is most likely due to accumulation of
drug in the group of older females. A study of the benzodiazepine
diazepam demonstrated a shorter t1/2 and a greater
plasma clearance in men in comparison to women (table
2)78. In a population of men and women receiving
olanzapine for Alzheimer’s Disease (AD) or schizophrenia, between one
and six samples were analyzed from each individual to determine
sex-differences in olanzapine clearance. Sex was found to be responsible
for 12% of variability in
olanzapine elimination. Men cleared olanzapine 38% faster than
women79. A natural pharmacokinetic study of
anticholinergic antidepressants in older adults looked for
sex-differences in serum concentrations. The ratio of absolute serum
concentration in comparison to the dose-adjusted serum concentration was
1.1-1.5-fold higher in women than in men for clomipramine and
trimipramine. This was despite a dose reduction in females who received
10-30% lower dose but still achieved serum levels equivalent to male
participants80. Findings of Mundo and Untereckeret al. suggest that clomipramine levels are not related to
sex81,82 but rather the metabolites of clomipramine
accumulate contributing to the higher plasma levels seen in women. A
second naturalistic study of antidepressants that examined 19,870 blood
samples failed to show a difference for the tricyclic antidepressants
clomipramine or fluvoxamine83 which is in keeping with
findings of Mundo and Unterecker81,82. However, in a
study that examined dose regimens of fluvoxamine separately, a dose
dependent sex difference in serum fluvoxamine concentration was
observed. At a 100 mg daily oral dose, women achieved higher serum
fluvoxamine concentrations than men, but with a 200 mg daily oral dose
the serum concentrations were no longer statistically significantly
different84. This may relate to a saturable
metabolizing enzyme that is in a greater concentration or more active in
men. Sex was correlated to paroxetine plasma concentrations in three
studies that examined the effect of sex on paroxetine pharmacokinetics.
In a study of 171 subjects aged ≥70 years, men had a higher paroxetine
Vd (461± 260 L) compared to women (346 ± 256
L)85. In a study of 1,677 older men and women the
serum concentration of paroxetine was 32% higher in women (86 nmol/L
versus 65 nmol/L, p<0.001)83. In a third
study of 70 patients the plasma concentration of paroxetine was higher
in women across age groups (28 versus 16 ng/mL;
p=0.001)86. The mean AUC and CMax for
bupropion, a mildly anticholinergic antidepressant, were higher in women
than men, however once these parameters were standardized for body
weight the statistical significance was lost87. For
bupropion, older women had a larger Vd and longer
t1/2 than young men. This does make it challenging to
know how much of the effect was attributable to sex versus
age88. Amitriptyline plasma levels were higher in
women in a study of 110 inpatients receiving routine doses of
amitriptyline89, but no significant sex-difference in
serum concentration of amitriptyline was noted in the study by Reiset al. 83. Nortriptyline plasma levels were
affected by sex with females experiencing higher plasma
levels90. Desipramine was shown to have a longer
elimination t1/2 and a faster oral clearance in older
men than in older women91. When examining risperidone
plasma concentrations, the only parameter to exhibit a statistically
significant difference between males and females was the plasma
concentration/dose ratio. When weight was used to adjust the plasma
concentration any difference was lost92. Many of these
psychoactive medications are metabolized by CYP2D6 and a sex-related
difference in CYP2D6 activity has not consistently been identified in
the literature93 which means there are likely other
sex-dependent mechanisms contributing to these pharmacokinetics
differences. In summary, while many sex-differences exist in the
pharmacokinetics of psychoactive anticholinergic medications, the
clinical relevance is unclear. The small increases in drug exposure that
were identified (most often by women) may help explain the increased
experience of adverse events by women94,95.