Sex differences in the gastrointestinal tract of rats and the implications for oral drug delivery

Abstract

Pre-clinical research often uses rodents as animal models to guide the selection of appropriate oral drug and dose selection in humans. However, traditionally, such research fails to consider the gastrointestinal differences between the sexes of rats and the impact on oral drug delivery. This study aimed to identify and characterise the potential sex-related differences in the gastrointestinal environment of sacrificed male and female Wistar rats. Their gastrointestinal tracts were excised and segmented into the stomach, duodenum, jejunum, ileum, caecum and colon. The respective contents and tissue sections were collected and analysed for pH, buffer capacity, surface tension, osmolality and relative P-glycoprotein (P-gp) expression. The pH in the stomach of females was found to be lower than in males. Female rats also exhibited a higher buffer capacity in the caecum and colon when compared with their male counterparts. Males were found to have a higher osmolality than females in the duodenum, ileum and colon. Significant sex differences (p < 0.05) in surface tension were observed in the ileum, where females exhibited a higher surface tension. Interestingly, female rats displayed significantly higher relative P-gp expression levels (p < 0.05) when compared with male rats in the duodenum (1.24 ± 0.85 vs. 0.36 ± 0.26), jejunum (1.45 ± 0.88 vs. 0.38 ± 0.26) and ileum (0.92 ± 0.43 vs. 0.40 ± 0.18) but not in the colon (0.5 ± 0.32 vs. 0.33 ± 0.16) segments. The work reported has demonstrated the stark physiological differences between male and female rats at a physiological level, indicating how the 'sex of the gut' could influence oral drug delivery. These findings, therefore, are of critical importance in pre-clinical research and drug development.

A systematic review and combined meta‐analysis of concentration of oral amisulpride

“…An animal model study suggested stark physiological differences between male and female rats, indicating that the ‘sex of the gut’ could influence oral drug delivery. Compared with male rats, females displayed significantly higher relative P‐gp expression levels in the duodenum, jejunum and ileum . Second, physiological factors resulting in sex‐related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate, and different gastric motility of females compared with males .…”

“…Compared with male rats, females displayed significantly higher relative P-gp expression levels in the duodenum, jejunum and ileum. 47 Second, physiological factors resulting in sex-related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate, and different gastric motility of females compared with males. 48 Given that >90% of amisulpride is excreted unchanged via the kidney, the lower glomerular filtration rate in females may contribute to differences as well.…”

P-glycoprotein expression in the gastrointestinal tract of male and female rats is influenced differently by food

“…Attempts have previously been made using Western blot analysis to investigate the distribution of P-gp in the rat intestinal tract, for instance; male Sprague-Dawley rats (Brady, 2002); fasted male Wistar rats (Valenzuela et al, 2004, Johnson et al, 2006, Wada et al, 2013; fed male and female Han-Wistar rats (MacLean et al, 2008); and fed male and female Wistar rats (Afonso-Pereira et al, 2018). The results of these studies, however, are inconsistent and further complicated by the differences in the reference proteins used to normalise transporter abundance.…”

“…In the literature, contradicting results have been reported regarding the segmental differences in Pgp expression along the small intestine. Several investigations have demonstrated that P-gp expression increases in the lower segments of the small intestine in rats (Hatton et al, 2015, Afonso-Pereira et al, 2018Mai et al, 2018) although others have reported that the highest expression can be determined towards the more proximal regions (Makhey et al, 1998, Yumoto et al, 1999, Stephens et al, 2002, Ho et al, 2003, Berggren et al, 2007. Assessing the methodologies used to determine P-gp in the literature, however, has revealed disparities in data collection regarding the reference protein, the strain of rat, the lack of consideration of potential sex differences and more notably, the influence of food on P-gp expression.…”

Gastrointestinal Tracking and Gastric Emptying of Coated Capsules in Rats with or without Sedation Using CT imaging

“…Among the different animals used in preclinical research, rodents make up approximately 95% of all laboratory animals [2]. Specifically, rats are one of the most widely used small animal models for the assessment of new pharmaceutical entities during pre-clinical studies [3][4][5][6][7][8][9]. The oral route is the most preferred and convenient way to administer drugs which can either be formulated to act locally in the gastrointestinal (GI) tract or be absorbed to achieve a systemic effect [10].…”