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% (control), 0.3%, 0.5%, 0.7% 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%, 0.5% 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 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 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.
Highlights
Peroral administration is the most convenient route of drug delivery due to its high patient compliance, flexibility in the design of dosage forms and the economical method of medicine manufacture
To identifying whether sex-specific differences in excipient-drug modulation translate from animals to humans at a physiological level, this study investigated the effects of pharmaceutically relevant concentrations of polyethylene glycol 400 (PEG 400) on cimetidine bioavailability in both healthy male and female subjects
In the absence of polyethylene glycol (PEG) 400, the total mean amount of cimetidine that was excreted in urine was similar in both males and females at 48% and 47% (w/w) of the administered dose respectively
Summary
Peroral administration is the most convenient route of drug delivery due to its high patient compliance, flexibility in the design of dosage forms and the economical method of medicine manufacture. Excipients, are broadly defined as “any component of a drug product other than the API” that are benign for human consumption [1,2]. These components are not expected to have a direct pharmacological effect but to instead, alter the physical properties of an oral dosage form (such as a tablet or capsule) to facilitate drug stability, appearance or taste, for example [3]. Polysorbates, mono- and disaccharide-based excipients have been shown to alter digoxin bioavailability via cell culture assays [10]. What is less understood is the role of excipient effects in differentially modifying drug pharmacokinetics in males and females
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