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.