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Cited by 13Drug Transport and Resistance MechanismsDrug Solubulity and Delivery SystemsPharmacogenetics and Drug Metabolism

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Sex-specific effects of excipients on oral drug bioavailability

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Mai, Yang, Madla, Christine M., Shao, Haibin, Qin, Yujia, Merchant, Hamid A., Murdan, Sudaxshina, Basit, Abdul W.·2022·International Journal of Pharmaceutics
DOI 10.1016/j.ijpharm.2022.122365
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Abstract

The mechanism of action of excipients eliciting sex differences in drug bioavailability is poorly understood. In this study, the excipients Cremophor RH 40 (PEG 40 hydrogenated castor oil), Poloxamer 188 (2-methyloxirane) and Tween 80 (polyoxyethylene (80) sorbitan monooleate) were screened at 0.07 - 5% concentrations for their effect on ranitidine bioavailability in male and female Wistar rats. We show that all excipient concentrations significantly increased ranitidine bioavailability in male, but not female, rats. The effect of these excipients on the intestinal efflux transporters P-glycoprotein (P-gp), breast cancer resistant protein (BCRP) and multi-drug resistant protein 2 (MRP2) were also monitored. Measured by ELISA assay, in male rats, peak reductions in intestinal P-gp protein expression occurred in the presence of 1% Cremophor RH 40 and Poloxamer 188 and 0.5% Tween 80. In contrast, no distinct changes were observed in female intestinal P-gp expression. Unlike P-gp, all excipients had a positive effect on MRP2 protein expression - albeit only in males - in a concentration-dependent manner. The excipients did not modulate intestinal BCRP protein expression in either sex. 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 significantly elevated in males, although PXR levels reduced at similar rates in both sexes. No significant effects were identified in oestradiol levels in male and female rats. It is clear that excipients are not inert and their pathway for modulating drug response is multi-dimensional and specific between sexes. This study showed that excipients increased drug bioavailability of a P-gp drug substrate due to its reductive effect on intestinal P-gp expression; we propose that this link may be due to the excipients modulating fundamental testosterone levels. Understanding the implication of excipients on intestinal physiology and hormone levels can therefore improve pharmaceutical design, clinical efficacy and instigate next generation personalised, sex-specific formulations.

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Metadata

Authors
Mai, Y., Madla, C. M., Shao, H., Qin, Y., Merchant, H. A., Murdan, S., & Basit, A. W.
Affiliations
  • Sun Yat-sen University (CN)
  • UCL School of Pharmacy (GB)
  • University of Huddersfield (GB)
Corresponding author
  • Mai, Yang
  • Basit, Abdul W.
ORCID
Venue
International Journal of Pharmaceutics
Publisher
Elsevier BV
Published
2022-12
Volume
629
Pages
122365
ISSN
0378-5173 (ISSN-L)
DOI
10.1016/j.ijpharm.2022.122365
OpenAlex
W4308077678
Cited by
13
References
3
Citations by year
2026: 1 · 2025: 7 · 2024: 3 · 2023: 2
FWCI
1.26
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Pharmaceutics (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Huddersfield Research Portal (University of Huddersfield) (publishedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Engineering and Physical Sciences Research Council (EP/L01646X)
  • National Natural Science Foundation of China (82003672)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
pharmaceutical excipients, sex differences, oral bioavailability, ranitidine, Cremophor RH40, poloxamer 188, Tween 80, P-glycoprotein, ABCG2, MRP2, testosterone, pregnane X receptor, estradiol
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Biological Availability, Estradiol, Excipients, Female, Male, Neoplasm Proteins, Polyethylene Glycols, Polysorbates, Ranitidine, Testosterone, Rats, Wistar, Poloxamer, Rats

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CoChat. (2026). Citation check: Sex-specific effects of excipients on oral drug bioavailability. https://app.cochat.ai/papers/10.1016/j.ijpharm.2022.122365
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Mai, Y., Madla, C. M., Shao, H., Qin, Y., Merchant, H. A., Murdan, S., & Basit, A. W. (2022). Sex-specific effects of excipients on oral drug bioavailability. International Journal of Pharmaceutics. https://doi.org/10.1016/j.ijpharm.2022.122365