Modulating intestinal absorption using pharmaceutical excipients

The objective of this thesis was to determine the effects of polyethylene glycol 400 (PEG 400) on the intestinal absorption of Biopharmaceutical Classification System (BCS) Class III drugs. The effect of different doses of PEG 400 (0.5, 0.75, 1, 1.25, 1.5 g) on the bioavailability of ranitidine was investigated in both male and female human subjects. An HPLC method for the analysis of ranitidine (and other H2 antagonists) and a mass spectrometry method for PEG 400 in urine were developed. In the male volunteers, the mean cumulative amount of unchanged ranitidine excreted in urine in the presence of 0.5, 0.75, 1, 1.25 and 1.5 g PEG 400 increased by 34, 63, 49, 43 and 6% over the control, whilst in the female volunteers, there were no differences compared to the control. 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 cumulative ranitidine excretion compared to control, p<0.05). The difference in bioavailability of ranitidine between males and females in the presence of PEG 400 was not due to differences in ranitidine metabolism or PEG 400 absorption. In separate human studies, the effect of different doses of PEG 400 (0, 0.5, 0.75, 1.0, 1.5 and 5 g) on the bioavailability of another BCS class III drug (cimetidine) was investigated. The results mirrored that noted with ranitidine, where lower doses of PEG 400 (< 1.5 g) enhanced the bioavailability of cimetidine in male subjects. In the female volunteers, there was no difference in bioavailability in the presence of PEG 400. The influence of PEG 400 on the bioavailability of ranitidine was also investigated in male and female rats. In a similar manner to man, there was no difference in the bioavailability of ranitidine in the absence of PEG 400. In the presence of PEG 400, there were some differences, however these were not significant. The plasma profiles of ranitidine in the male rats exhibited a single peak compared to the female rats which had multiple peaks. Mechanistic studies were carried out in an attempt to explain the findings. Cimetidine, ranitidine and PEG analogues were screened for their P-glycoprotein (P-gp) activity using an ATPase assay. Ranitidine and PEG 400 stimulated P-gp activity whilst cimetidine and PEG 200 did not. Subsequently the effects of PEG 400 on the efflux transport of ranitidine and cimetidine was investigated using Caco-2 cell lines. PEG 400 did not change the Transepithelial Electrical Resistance and mannitol flux of the Caco-2 cell lines indicating that PEG 400 does not influence paracellular transport. An indicative increased absorptive effect, though not significant, was observed for the transport of ranitidine in the presence of PEG 400 possibly due to the effect of PEG 400 on efflux transporters such as P-gp and Breast Cancer Resistance Protein (BCRP). These findings challenge the 'inert/inactive' status of excipients such as PEG 400. The results of this thesis have implications for the use of PEG 400 in dosage forms (for example when compounds are being considered for biowaivers) and also highlight the importance of gender studies in pharmacokinetics