Prandial state and biological sex modulate clinically relevant efflux transporters to different extents in Wistar and Sprague Dawley rats

P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) are clinically relevant efflux transporters implicated in the oral absorption of many food and drug substrates. Here, we hypothesised that food intake could influence protein and mRNA intestinal expression of P-gp/abcb1a, BCRP/abcg2, and MRP2/abcc2 differently in male and female Wistar and Sprague Dawley rats. To test this hypothesis, we used enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) to quantify the protein and mRNA intestinal expression of these transporters, respectively.

Highlights

• Food intake influences the expression of P-gp, BCRP, and MRP2 with differing responses.
• The sex (male versus female) and strain (Wistar vs Sprague Dawley) also affected the P-gp, BCRP, and MRP2 levels.
• Positive correlation was found between P-gp/abcb1a, BCRP/abcg2, and MRP2/abcc2 expression measured by ELISA and PCR.
• Food, sex, and strain should be considered in the design of preclinical experiments into efflux transporter expression.

Our study found food and sex differences in P-gp expression, whereby in the fed state P-gp expression decreased in male Wistar rats, but P-gp expression increased in females. In the fed state, BCRP expression increased in both male and female Wistar rats, compared with the fasted state. In contrast, no sex differences or food effect differences were seen in Sprague Dawley rats for P-gp and BCRP expression. On the other hand, in the fed state, MRP2 expression was higher in male and female Wistar and Sprague Dawley rats when compared with the fasted state. Sex differences were also observed in the fasted state. Overall, significant strain differences were reported for P-gp, BCRP and MRP2 expression. Strong to moderate positive linear correlations were found between ELISA and PCR quantification methods. ELISA may be more useful than PCR as it reports protein expression as opposed to transcript expression. Researchers must consider the influence of sex, strain and feeding status in preclinical studies of P-gp, BCRP and MRP2 drug substrates.

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Francesca K.H. Gavins, Liu Dou, Yujia Qin, Christine M. Madla, Sudaxshina Murdan, Abdul W. Basit, Yang Mai, Mine Orlu, Prandial state and biological sex modulate clinically relevant efflux transporters to different extents in Wistar and Sprague Dawley rats, Biomedicine & Pharmacotherapy, Volume 160, 2023, 114329, ISSN 0753-3322,
https://doi.org/10.1016/j.biopha.2023.114329.