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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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Research works printed but not linked: 49

  1. Afonso-Pereira, 2016, Sex differences in excipient effects: Enhancement in ranitidine bioavailability in the presence of polyethylene glycol in male, but not female, rats, Int. J. Pharm., 506, 237, 10.1016/j.ijpharm.2016.04.022 · DOI
  2. Altintas Aykan, 2019, The effects of administration of Vitamin D, infliximab, and leflunomide on testosterone concentrations in rats under atorvastatin therapy, Eurasian J. Med., 51, 224, 10.5152/eurasianjmed.2019.18481 · DOI
  3. Ashiru, 2007, Simple and universal HPLC-UV method to determine cimetidine, ranitidine, famotidine and nizatidine in urine: application to the analysis of ranitidine and its metabolites in human volunteers, J. Chromatogr. B Analyt Technol. Biomed. Life Sci., 860, 235, 10.1016/j.jchromb.2007.10.029 · DOI
  4. Ashiru, 2008, Polyethylene glycol 400 enhances the bioavailability of a BCS class III drug (ranitidine) in male subjects but not females, Pharm. Res., 25, 2327, 10.1007/s11095-008-9635-y · DOI
  5. Barreto-Ojeda, 2018, Coarse-grained molecular dynamics simulations reveal lipid access pathways in P-glycoprotein, J. Gen. Physiol., 150, 417, 10.1085/jgp.201711907 · DOI
  6. Basit, 2001, The effect of polyethylene glycol 400 on gastrointestinal transit: implications for the formulation of poorly-water soluble drugs, Pharm. Res., 18, 1146, 10.1023/A:1010927026837 · DOI
  7. Basit, 2002, Pharm Res., 19, 1368, 10.1023/A:1020315228237 · DOI
  8. Bogman, 2005, P-glycoprotein and surfactants: effect on intestinal talinolol absorption, Clin. Pharmacol. Ther., 77, 24, 10.1016/j.clpt.2004.09.001 · DOI
  9. Bourdet, 2006, Intestinal absorptive transport of the hydrophilic cation ranitidine: a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in Caco-2 cells, Pharm. Res., 23, 1178, 10.1007/s11095-006-0204-y · DOI
  10. Bourdet, 2006, Saturable absorptive transport of the hydrophilic organic cation ranitidine in Caco-2 cells: role of pH-dependent organic cation uptake system and P-glycoprotein, Pharm. Res., 23, 1165, 10.1007/s11095-006-0251-4 · DOI
  11. Coles, 2009, Estradiol and progesterone-mediated regulation of P-gp in P-gp overexpressing cells (NCI-ADR-RES) and placental cells (JAR), Mol. Pharm., 6, 1816, 10.1021/mp900077q · DOI
  12. Collett, 1999, Modulation of the permeability of H2 receptor antagonists cimetidine and ranitidine by P-glycoprotein in rat intestine and the human colonic cell line Caco-2, J. Pharmacol. Exp. Ther., 288, 171
  13. Dahan, 2009, The H2 receptor antagonist nizatidine is a P-glycoprotein substrate: characterization of its intestinal epithelial cell efflux transport, AAPS J., 11, 205, 10.1208/s12248-009-9092-5 · DOI
  14. Dintaman, 1999, Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), Pharmaceut Res., 16, 1550, 10.1023/A:1015000503629 · DOI
  15. Evseenko, 2007, Independent regulation of apical and basolateral drug transporter expression and function in placental trophoblasts by cytokines, steroids, and growth factors, Drug Metab. Dispos., 35, 595, 10.1124/dmd.106.011478 · DOI
  16. Flanagan, 2019, Potential for pharmaceutical excipients to impact absorption: a mechanistic review for BCS Class 1 and 3 drugs, Eur. J. Pharm. Biopharm., 141, 130, 10.1016/j.ejpb.2019.05.020 · DOI
  17. Freire, 2011, Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery, Int. J. Pharm., 415, 15, 10.1016/j.ijpharm.2011.04.069 · DOI
  18. Geick, 2001, Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin, J. Biol. Chem., 276, 14581, 10.1074/jbc.M010173200 · DOI
  19. Hafsa, 2015, Influence of poloxamer 188 on the intestinal transport of diltiazem hydrochloride, Int. J. Inno Res. Sci. Eng. Tech., 4, 6922, 10.15680/IJIRSET.2015.0408181 · DOI
  20. Hodaei, 2015, Effects of polyethylene glycols on intestinal efflux pump expression and activity in Caco-2 cells, Braz. J. Pharm. Sci., 51, 745, 10.1590/S1984-82502015000300026 · DOI
  21. Holmstock, 2013, PXR/CYP3A4-humanized mice for studying drug-drug interactions involving intestinal P-glycoprotein, Mol. Pharm., 10, 1056, 10.1021/mp300512r · DOI
  22. International Transporter, 2010, Membrane transporters in drug development, Nat. Rev. Drug Discov., 9, 215, 10.1038/nrd3028 · DOI · Paper page
  23. Jarvinen, 2018, Efflux transport of estrogen glucuronides by human MRP2, MRP3, MRP4 and BCRP, J. Steroid Biochem. Mol. Biol., 178, 99, 10.1016/j.jsbmb.2017.11.007 · DOI
  24. Li-Blatter, 2009, Detergents as intrinsic P-glycoprotein substrates and inhibitors, BBA, 1788, 2335, 10.1016/j.bbamem.2009.07.010 · DOI
  25. MacLean, 2008, Closing the gaps: a full scan of the intestinal expression of P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in male and female rats, Drug Metab. Dispos., 36, 1249, 10.1124/dmd.108.020859 · DOI
  26. Madla, 2022, Sex Differences in Intestinal P-Glycoprotein Expression in Wistar versus Sprague Dawley Rats, Pharmaceutics, 14, 10.3390/pharmaceutics14051030 · DOI
  27. Mai, 2017, Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal, Eur. J. Pharm. Sci., 107, 249, 10.1016/j.ejps.2017.07.009 · DOI
  28. Mai, 2018, An animal's sex influences the effects of the excipient PEG 400 on the intestinal P-gp protein and mRNA levels, which has implications for oral drug absorption, Eur. J. Pharm. Sci., 10.1016/j.ejps.2018.04.021 · DOI
  29. Mai, 2018, Establishing an in vitro permeation model to predict the in vivo sex-related influence of PEG 400 on oral drug absorption, Int. J. Pharm., 542, 280, 10.1016/j.ijpharm.2018.03.002 · DOI
  30. Mai, 2019, Sex-Dependence in the Effect of Pharmaceutical Excipients: Polyoxyethylated Solubilising Excipients Increase Oral Drug Bioavailability in Male but not Female Rats, Pharmaceutics, 11
  31. Mai, 2020, Boosting drug bioavailability in men but not women through the action of an excipient, Int. J. Pharm., 587, 10.1016/j.ijpharm.2020.119678 · DOI · Paper page
  32. Martinez, 2022, A critical overview of the biological effects of excipients (Part I): impact on gastrointestinal absorption, AAPS J., 24, 60, 10.1208/s12248-022-00711-3 · DOI
  33. Moesgaard, 2022, Mechanism behind Polysorbates' Inhibitory Effect on P-Glycoprotein, Mol. Pharm., 10.1021/acs.molpharmaceut.2c00074 · DOI
  34. Mohammadzadeh, 2014, Reduced ABCB1 expression and activity in the presence of acrylic copolymers, Adv Pharm Bull, 4, 219
  35. Mutoh, 2006, Estrogen-mediated post transcriptional down-regulation of P-glycoprotein in MDR1-transduced human breast cancer cells, Cancer Sci., 97, 1198, 10.1111/j.1349-7006.2006.00300.x · DOI
  36. Nerurkar, 1996, The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system, Pharm. Res., 13, 528, 10.1023/A:1016033702220 · DOI
  37. Rege, 2002, Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers, Eur. J. Pharm. Sci., 16, 237, 10.1016/S0928-0987(02)00055-6 · DOI
  38. Reker, 2019, “Inactive” ingredients in oral medications, Sci. Transl. Med., 11
  39. Reker, 2020, Machine learning uncovers food- and excipient-drug interactions, Cell Rep., 30, e3714
  40. Rigalli, 2019, Modulation of ABC transporters by nuclear receptors: physiological, pathological and pharmacological aspects, Curr. Med. Chem., 26, 1079, 10.2174/0929867324666170920141707 · DOI
  41. Sachs-Barrable, 2007, Lipid excipients Peceol and Gelucire 44/14 decrease P-glycoprotein mediated efflux of rhodamine 123 partially due to modifying P-glycoprotein protein expression within Caco-2 cells, J. Pharm. Pharm. Sci., 10, 319
  42. Schulze, 2003, Concentration-dependent effects of polyethylene glycol 400 on gastrointestinal transit and drug absorption, Pharm. Res., 20, 1984, 10.1023/B:PHAM.0000008046.64409.bd · DOI
  43. Shchulkin, 2017, The role of testosterone in the regulation of P-glycoprotein functioning, Biol. Bull., 44, 524, 10.1134/S1062359017050168 · DOI
  44. Sun, 2004, Specific role of polysorbate 80 coating on the targeting of nanoparticles to the brain, Biomaterials, 25, 3065, 10.1016/j.biomaterials.2003.09.087 · DOI
  45. Wandel, 2003, “Inactive” excipients such as Cremophor can affect in vivo drug disposition, Clin. Pharmacol. Ther., 73, 394, 10.1016/S0009-9236(03)00010-9 · DOI
  46. Wang, 2006, Regulation of BCRP/ABCG2 expression by progesterone and 17beta-estradiol in human placental BeWo cells, Am. J. Physiol. Endocrinol. Metab., 290, E798, 10.1152/ajpendo.00397.2005 · DOI
  47. Yu, 2021, Excipient innovation through precompetitive research, Pharm. Res., 38, 2179, 10.1007/s11095-021-03157-y · DOI
  48. Zhang, 2010, PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel, Comput. Methods Programs Biomed., 99, 306, 10.1016/j.cmpb.2010.01.007 · DOI
  49. Zhang, 2003, Commonly used surfactant, Tween 80, improves absorption of P-glycoprotein substrate, digoxin, in rats, Arch. Pharm. Res., 26, 768, 10.1007/BF02976689 · DOI

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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