Effect of Food and an Animal’s Sex on P-Glycoprotein Expression and Luminal Fluids in the Gastrointestinal Tract of Wistar Rats

Liu, Dou; Gavins, Francesca K.H.; Yang, Ming; Madla, Christine M.; Taherali, Farhan; Orlu, Mine; Murdan, Sudaxshina; Basit, Abdul W.

doi:10.3390/pharmaceutics12040296

Cited by 21 publications

(23 citation statements)

References 47 publications

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“…This difference could also be responsible for differences in the concentration of drug and PEG 400 in the intestinal lumen in humans, which in turn could affect transit and permeability between the sexes. If we take into consideration that we are observing similar effects of PEG 400 in rats and humans, and given the considerable difference between the rat and human GI luminal environment, we do not believe sex differences in GI luminal environment (Dou et al, 2020) could be the cause for pronounced difference in the way males and females of both species react to PEG 400.…”

Section: Discussionmentioning

confidence: 98%

“…In order to understand the potential mechanism as to why sex-related differences in drug bioavailability may occur, a number of studies have demonstrated that the intestinal efflux transporter, P-glycoprotein (P-gp) is differentially expressed between the sexes in an animal model (Dou et al, 2020;Dou et al, 2018;Mai et al, 2018a;Mai et al, 2018c). P-gp is postulated to serve as an essential protective mechanism in the intestinal luminal environment by heavily mediating oral drug absorption.…”

Section: Introductionmentioning

confidence: 99%

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Boosting drug bioavailability in men but not women through the action of an excipient

Yang

Ashiru‐Oredope

Yao

et al. 2020

International Journal of Pharmaceutics

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Active pharmaceutical ingredients are routinely formulated with a range of excipients in the manufacture of drug products. Excipients are considered to be inert components of the formulations, although recent research has contested its inactive behaviour. This study investigated the effect of the excipient polyethylene glycol 400 (PEG 400) on the oral bioavailability and intestinal permeability of cimetidine in male and female human volunteers.Aqueous solutions of cimetidine with pharmaceutically relevant concentrations of PEG 400 at 0% w/v (control), 0.3% w/v, 0.5% w/v, 0.7% w/v and 1.0% w/v were orally administered to both sexes. Urine samples were then collected and assayed for the determination of cimetidine which reflected oral bioavailability. This human study showed that PEG 400 at 0.3% w/v, 0.5% w/v and 0.7% w/v concentrations significantly increased cimetidine bioavailability by 34%, 58% and 41% respectively, although this enhancement was only demonstrated in men and not women (p < 0.05). Ussing chamber transport studies with male human jejunal tissues revealed that cimetidine permeability increased by 26%, 48% and 29% with PEG 400 at 0.3% w/v, 0.5% w/v and 0.7% w/v respectively (p < 0.05). No such enhancement was demonstrated in female tissues (p > 0.05). We have shown that PEG 400 interacts with intestinal P-glycoprotein (P-gp) expression differently in males and females. The mechanistic action of PEG 400 at gut level was further investigated on human jejunal tissues following the pre-treatment of the P-gp inhibitor PSC 833 (valspodar) on the transport of cimetidine. When intestinal P-gp was inhibited, the sex-and dose-dependent modulatory effect of PEG 400 with cimetidine was completely eradicated, thus confirming that PEG 400 has a modulatoryrather than inhibitory effect on P-gp. In sum, the widely used excipient PEG 400 is not inert at pharmaceutically relevant concentrations and its modulatory effect is demonstrated at a human clinical level. Such pharmacological effects, however, are sex-and dose-dependent via its modulation on intestinal P-gp, as evidenced by the boost in cimetidine bioavailability only in male human volunteers. As such, these findings should be carefully considered towards the co-formulation of PEG 400 with drugs that are P-gp substrates.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Boosting drug bioavailability in men but not women through the action of an excipient

Yang

Ashiru‐Oredope

Yao

et al. 2020

International Journal of Pharmaceutics

Self Cite

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show abstract

“…This difference could also be responsible for differences in the concentration of drug and PEG 400 in the intestinal lumen in humans, which in turn could affect transit and permeability between the sexes. If we take into consideration that we are observing similar effects of PEG 400 in rats and humans, and given the considerable difference between the rat and human GI luminal environment, we do not believe sex differences in GI luminal environment [28] could be the cause for pronounced difference in the way males and females of both species react to PEG 400.…”

Section: Discussionmentioning

confidence: 98%

“…In order to understand the potential mechanism as to why sex-related differences in drug bioavailability may occur, a number of studies have demonstrated that the intestinal efflux transporter, P-glycoprotein (P-gp) is differentially expressed between the sexes in an animal model [28][29][30][31]. P-gp is postulated to serve as an essential protective mechanism in the intestinal luminal environment by heavily mediating oral drug absorption.…”

Section: Introductionmentioning

confidence: 99%

Boosting drug bioavailability in men but not women through the action of an excipient

Basit

Yang

Ashiru‐Oredope

et al. 2020

Proceedings of the 1st International Electronic Conference on Pharmaceutics

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Active pharmaceutical ingredients are routinely formulated with a range of excipients in the manufacture of drug products. Excipients are considered to be inert components of the formulations, although recent research has contested its inactive behaviour. This study investigated the effect of the excipient polyethylene glycol 400 (PEG 400) on the oral bioavailability and intestinal permeability of cimetidine in male and female human volunteers. Aqueous solutions of cimetidine with pharmaceutically relevant concentrations of PEG 400 at 0% w/v (control), 0.3% w/v, 0.5% w/v, 0.7% w/v and 1.0% w/v were orally administered to both sexes. Urine samples were then collected and assayed for the determination of cimetidine which reflected oral bioavailability. This human study showed that PEG 400 at 0.3% w/v, 0.5% w/v and 0.7% w/v concentrations significantly increased cimetidine bioavailability by 34%, 58% and 41% respectively, although this enhancement was only demonstrated in men and not women (p < 0.05). Ussing chamber transport studies with male human jejunal tissues revealed that cimetidine permeability increased by 26%, 48% and 29% with PEG 400 at 0.3% w/v, 0.5% w/v and 0.7% w/v respectively (p < 0.05). No such enhancement was demonstrated in female tissues (p > 0.05). We have shown that PEG 400 interacts with intestinal Pglycoprotein (P-gp) expression differently in males and females. The mechanistic action of PEG 400 at gut level was further investigated on human jejunal tissues following the pre-treatment of the Pgp inhibitor PSC 833 (valspodar) on the transport of cimetidine. When intestinal P-gp was inhibited, the sex-and dose-dependent modulatory effect of PEG 400 with cimetidine was completely eradicated, thus confirming that PEG 400 has a modulatory-rather than inhibitory-effect on Pgp. In sum, the widely used excipient PEG 400 is not inert at pharmaceutically relevant concentrations and its modulatory effect is demonstrated at a human clinical level. Such pharmacological effects, however, are sex-and dose-dependent via its modulation on intestinal Pgp, as evidenced by the boost in cimetidine bioavailability only in male human volunteers. As such, these findings should be carefully considered towards the co-formulation of PEG 400 with drugs that are P-gp substrates.

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“…Thus, specialists in the field must rely on their knowledge to adapt formulations to suit the pharmaceutical needs of the individual [50]. There are many factors to consider during personalised formulation design, some include: patient's swallowing capacity, flavour preferences, required drug dose, required drug release kinetics, presence of disease, sex, age, motor skills, and coadministered medications [184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199]. ML has the capacity to consider all these factors and predict optimal formulation design features based on an individual's requirements [154,[200][201][202].…”

Section: Machine Learning In the Pre-printing Stagementioning

confidence: 99%

Harnessing artificial intelligence for the next generation of 3D printed medicines

Elbadawi

McCoubrey

Gavins

et al. 2021

Advanced Drug Delivery Reviews

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110

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Effect of Food and an Animal’s Sex on P-Glycoprotein Expression and Luminal Fluids in the Gastrointestinal Tract of Wistar Rats

Cited by 21 publications

References 47 publications

Boosting drug bioavailability in men but not women through the action of an excipient

Boosting drug bioavailability in men but not women through the action of an excipient

Boosting drug bioavailability in men but not women through the action of an excipient

Harnessing artificial intelligence for the next generation of 3D printed medicines

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