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.