Effect of sex on the absorption of anticholinergic medications
Some, but not all, studies show that gastric and colonic emptying is
slowed in women, potentially increasing oral bioavailability of
drugs28–34. When stratified by age, the rate of
gastric emptying for postmenopausal women and men is
similar35 and significantly faster than premenopausal
(younger) women33. Gastric pH is higher in
females36 which may increase absorption of basic
medications such as tricyclic antidepressants, many of which are quite
potently anticholinergic. This difference in gastric pH was quantified
by Feldman and Barnett in 1991 as a mean pH of 2.79 for women and 2.16
for men, which was due to reduced acid secretion in
women37. The greater stomach size in men allows for
more fluid to be contained therein which can improve both the rate and
extent of dissolution of introduced oral dosage forms for men in
comparison to women. In contrast, intestinal pH has not been found to
differ by sex38,39. CYP enzymes exist in intestinal
enterocytes, where they contribute to the first pass metabolism of
orally administered drugs. Intestinal CYP3A4 metabolism inconsistently
exhibits sex differences. Early reports suggested that the CYP3A4
substrates verapamil and midazolam had increased bioavailability in
women40–42. However, in 2005 a detailed analysis of
duodenal punch biopsies from 48 men and 45 women found no clinically
meaningful sex difference in intestinal CYP3A4
content43. Krecic-Shepard et al. observed that
oral verapamil was cleared more quickly in men with no significant
difference after IV administration, suggesting some differences in
intestinal metabolism exist44 which could affect those
anticholinergic medications that are substrates of CYP3A4. In females,
the CYP3A4 content in the intestine has been shown to decrease by
approximately 20% after menopause43 which may reduce
CYP3A4 metabolism and affect the sex-difference in CYP3A4
pharmacokinetics in older women. This decrease in intestinal CYP3A4 in
postmenopausal women has not been shown to be clinically meaningful to
date. Similarly, male versus female differences in the drug efflux pump
ABCB1 (p-glycoprotein) in the intestinal lumen have been hypothesized as
a contributor to differences in drug absorption between
sexes43 but this too has not been demonstrated to be
clinically meaningful in studies to date.