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

Abstract

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.

Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter

“…Pharmaceutical excipients have also been reported to actively modulate intestinal P-gp differently in the sexes which consequently results in differing responses to P-gp drug substrates. For example, when 0.75 g of PEG 400 was co-formulated with P-gp drug substrates ranitidine 11 and cimetidine, 12 oral drug absorption increased by 63 and 41% respectively, although such a phenomenon was only demonstrated in healthy male volunteers, not females. The potential mechanism of such sex-specific effects was attributed to the pharmaceutical excipient modulating the functionality of intestinal P-gp.…”

“… 9 , 10 The bioavailability of other P-gp substrates, ranitidine and cimetidine, was also reported to be different in males and females in the presence of polyethylene glycol (PEG) 400. 11 , 12 Interestingly, several studies have shown that P-gp expression in male and female rats is different, 12 − 14 which can affect the oral bioavailability of P-gp drug substrates. 15 , 16 However, the physiological understanding of preclinical animal models, such as rats, is poor in line with the translation to first-in-human trials.…”

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

“…Even seemingly insignificant changes to formulation design can significantly affect the final medicine characteristics and in vivo behaviour. For example, tablet geometry can considerably affect drug dissolution rate, and the choice of excipients can affect bioavailability [182,183]. In pharmaceutical 3DP, formulations are often personalised and thus different from one batch to the next.…”

Fetal glucocorticoid exposure leads to sex‐specific changes in drug‐transporter function at the blood‐brain barrier in juvenile guinea pigs

“…[26][27][28][29][30] Thus, prenatal exposure to sGCs that leads to long-term changes in BBB function may have consequences for post-natal drug disposition. There is also evidence for sex-specific expression and function of drug transporters in the brain and other tissues, [31][32][33][34] however, virtually nothing is known about potential sex differences at the developing BBB. In the present study, we hypothesized that prenatal exposure to multiple and single courses of sGCs would lead to long-term changes in P-gp/Abcb1 and BCRP/Abcg2 expression and function substrates.…”