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

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 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. As such, these findings should be carefully considered towards the co-formulation of PEG 400 with drugs that are P-gp substrates.

The effect of polyoxyethylene polymers on the transport of ranitidine in Caco-2 cell monolayers.

Previous in vivo studies using PEG 400 showed an enhancement in the bioavailability of ranitidine. This study investigated the effect of PEG 200, 300 and 400 on ranitidine transport across Caco-2 cells. The effect of PEG polymers (20%, v/v) on the bi-directional flux of (3)H-ranitidine across Caco-2 cell monolayers was measured. The concentration dependence of PEG 400 effects on ranitidine transport was also studied. A specific screen for P-glycoprotein (P-gp) activity was used to test for an interaction between PEG and P-gp. In the absence of PEG, ranitidine transport showed over 5-fold greater flux across Caco-2 monolayers in the secretory than the absorptive direction; efflux ratio 5.38. PEG 300 and 400 significantly reduced this efflux ratio (p<0.05), whereas PEG 200 had no effect (p>0.05). In concordance, PEG 300 and 400 showed an interaction with the P-gp transporter, whereas PEG 200 did not. Interestingly, with PEG 400 a non-linear concentration dependence was seen for the inhibition of the efflux ratio of ranitidine, with a maxima at 1%, v/v (p<0.05). The inhibition of ranitidine efflux by PEG 300 and 400 which interact with P-gp provides a mechanism that may account for the observations of ranitidine absorption enhancement by PEG 400 in vivo.