Polyethylene Glycol 400 Enhances the Bioavailability of a BCS Class III Drug (Ranitidine) in Male Subjects but Not Females

Abstract

All doses of PEG 400 enhanced the bioavailability of ranitidine in male subjects but not females, with the most pronounced effect in males noted with the 0.75 g dose of PEG 400 (63% increase in bioavailability compared to control, p < 0.05). These findings have significant implications for the use of PEG 400 in drug development and also highlight the importance of gender studies in pharmacokinetics.

Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs

“…The low molecular weight PEGs (<600) are liquids in nature and commonly employed as a vehicle to enhance the solubility and bioavailability of poorly water-soluble drugs (29). However, recent studies have revealed that PEG 400 at the doses relevant to pharmaceutical formulations stimulates GI motility and accelerates small intestine transit, leading to lower drug bioavailability (15,16,20). Like sorbitol and mannitol, PEGs cannot be absorbed in the intestine and thus retains fluid by osmotic action.…”

“…Additionally, PEGs have been demonstrated to interact with certain transporters, particularly efflux transporters such as Pglycoprotein (P-gp) (28). Table II provides the summary data of three bioavailability studies previously conducted on ranitidine with PEG 400 (15,16,20). In these studies, various amounts of PEG 400 were added to ranitidine solutions (in orange juice or water) and administered to healthy volunteers.…”

“…For male subjects, ranitidine absorption was increased with the dose of PEG 400 over the range of 0.5-1.5 g, peaking at 0.75 g followed by a gradual decline to the baseline at 1.5 g. However, for female subjects, reduced ranitidine bioavailability was found in the presence of PEG 400 between 0.5 and 1.5 g. The observed gender difference in ranitidine bioavailability has been attributed, in part, to the potential interplay between the osmotic effect of PEG 400 on small intestine transit and its modulation of intestinal permeability via inhibition of P-gp efflux transport and/or alteration on membrane fluidity (16,20). Specifically, it was postulated that the increased ranitidine bioavailability in male subjects with PEG 400 at low doses (e.g., 0.5-1.5 g) was due to the ability of this excipient to modulate intestinal permeability, an absorption-enhancing mechanism that was, however, overshadowed at higher doses (≥2.5 g) by the marked acceleration of transit time in the small intestine (16,20). On the other hand, female subjects might have higher proportion of gut efflux transporters including breast cancer resistance protein (BCRP) that could contribute to the differences in bioavailability observed in this study (20).…”

“…Historically, excipients were considered inert substances that could be used mainly in the manufacture of drug products as diluents, fillers, binders, lubricants, coatings, solvents, and dyes (7). However, with the advances in pharmaceutical science, some "active" excipients have been found to be capable of influencing drug absorption or bioavailability through a variety of mechanisms, such as modification in solubility/dissolution, change in intestinal permeability (including transporters), and modulation of gastrointestinal (GI) motility (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). To further investigate the effects of "active" excipients on the absorption of BCS class III drugs, this paper examines those that may modulate GI motility and affect the transit time of drugs in the gut.…”

“…Both ranitidine and cimetidine are BCS class III drugs that exhibit site-dependent absorption characteristics (19). Polyethylene glycol (PEG) 400, a commonly used excipient for enhancing drug solubility, was also found to accelerate small intestine transit and adversely influence the absorption of ranitidine (15,16,20). It is noted that all of these excipients (sorbitol, mannitol, and PEG 400) are osmotically active at the amounts relevant to those used in pharmaceutical formulations (21).…”