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.