Madla, Christine May Caplis; (2024) An investigation into the sex-specific effects of excipients on oral drug bioavailability. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The abundant components that complete a medicine are pharmaceutical excipients. These are defined to be inert agents only included with an active pharmaceutical ingredient to serve its intended function. Less is known on the potential influence of excipients on biological sex. To model for the human response, this PhD thesis identified that the Wistar rat was the most appropriate preclinical rat strain to investigate for sex differences in intestinal P-glycoprotein (P-gp) expression. This PhD thesis has further demonstrated that commonly used polyoxyethylated excipients (polyethylene glycol (PEG) 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increased the oral bioavailability of ranitidine, a P-gp drug substrate. However, such excipient effects were only prevalent in male but not female Wistar rats. P-gp and other clinically relevant intestinal efflux membrane transporters (multidrug resistance-associated protein 2, MRP2; and breast cancer resistance protein, BCRP) were quantified to understand the influence of Cremophor RH 40, Poloxamer 188 and Tween 80 exposure on drug absorption. In male Wistar rats, the presence of excipients decreased intestinal P-gp expression. This consequently reduced the efflux of its drug substrate, ranitidine, and thus, increased drug absorption. No excipient effects were observed in female intestinal P-gp expression. Opposite to P-gp, all excipients increased MRP2 protein expression, again, in male but not female Wistar rats. The excipients explored did not modulate intestinal BCRP expression in both sexes. To explore mechanistic pathways, endogenous hormones and a nuclear receptor (testosterone, oestradiol and pregnane-X receptor, PXR) that are purported to regulate intestinal efflux membrane transporter expression were also quantified. In the presence of all excipients, testosterone levels were significantly elevated in males, although PXR levels was reduced to similar levels in both sexes. No significant effects were identified in oestradiol levels in male and female Wistar rats. Excipients have been identified to consequently not be inert and their mechanism for modulating drug bioavailability is multidimensional, and specific in the sexes. The collection of studies showed that excipients increased drug bioavailability of a P-gp drug substrate due to its reductive effect on intestinal P-gp expression. This thesis proposes that the causality is specifically due to excipients actively modulating fundamental testosterone levels. Understanding the implication of excipients on intestinal physiology and hormone levels can therefore improve pharmaceutical design, clinical efficacy and instigate the next generation personalised, sex-specific formulations.

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