Effect of sex on the metabolism and transport of anticholinergic
medications
Several studies support that hepatic CYP metabolism varies between men
and women although the clinical significance is a challenge to
understand fully. The most abundant hepatic CYP enzyme is CYP3A4 and it
is involved in the metabolism of some anticholinergic
medications. In humans CYP3A4 has
a higher level of protein expression in the female
liver49. Consistent with the expression data, CYP3A4
oxidation was reported to be more efficient in
women40,50 with a two-fold higher CYP3A4 hepatic
content and 50% increase in the metabolizing
capacity51 but this finding has not been replicated in
other scientific investigations52,53. An in
vitro study from samples of 43 healthy livers in subjects between the
ages of 27 and 83 showed a 24% increase in CYP3A4 activity identified
by erythromycin N-demethylation in females54. Women
have an increase in CYP3A4 activity measured as a greater clearance of
CYP3A4 substrates such as the weakly anticholinergic antihypertensive
medication nifedipine55 and the weakly anticholinergic
sedative alprazolam56. On average, the
weight-normalized clearance of alprazolam and nifedipine is mainly due
to CYP3A4 and is 20% to 30% higher in young women than in young men.
This difference applies to both parenteral and oral administration and
is not explained away by p-glycoprotein activity57.
For context, CYP3A4 activity has been studied in relation to metabolism
of some non-anticholinergic agents, such as midazolam and clindamycin.
Meta-analysis suggests that women exhibit a 16% higher weight-corrected
oral clearance of midazolam (p < 0.001) and 20% higher
systemic clearance (p = 0.002) than men. No significant difference in
the area under the curve (AUC) after oral dosing of midazolam is found
but after intravenous (IV) administration women showed lower AUC than
men (p = 0.02). No sex-dependent differences were observed in midazolam
bioavailability58. Clindamycin does not show any sex
difference in its oral pharmacokinetics59. The study
of midazolam and clindamycin confirm sex variability in CYP3A4
metabolism but fail to demonstrate any consistent sex-differences. In
investigations of sex-differences in CYP2C19 activity,
4-hydroxymephenytoin and zonisamide failed to show any
sex-differences60,61.
A Spanish study found higher CYP2D6 activity in
women62.
Sex differences have been demonstrated in the glucuronidation of some
medications (acetaminophen) but not others
(zidovudine)63–65, suggesting that sex differences in
drug conjugation exist and are drug-dependent. To date, no
anticholinergic agents have been explored with respect to
glucuronidation. Clearance of some non-anticholinergic drugs by
glucuronidation have been shown to be increased in men in comparison to
women including oxazepam50,
temazepam66 and acetaminophen67.
With regard to catechol-O-methyltransferase activity, liver tissue from
female subjects exhibited approximately 25% lower activity than samples
from male subjects68. There is a two-fold greater
expression of hepatic p-glycoprotein in men compared to
women69 with unclear clinical relevance.