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Interaction of Commonly Used Oral Molecular Excipients with P-glycoprotein

  • Research Article
  • Theme: The Biological Effect of Pharmaceutical Excipients
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Abstract

P-glycoprotein (P-gp) plays a critical role in drug oral bioavailability, and modulation of this transporter can alter the safety and/or efficacy profile of substrate drugs. Individual oral molecular excipients that inhibit P-gp function have been considered a mechanism for improving drug absorption, but a systematic evaluation of the interaction of excipients with P-gp is critical for informed selection of optimal formulations of proprietary and generic drug products. A library of 123 oral molecular excipients was screened for their ability to inhibit P-gp in two orthogonal cell-based assays. β-Cyclodextrin and light green SF yellowish were identified as modest inhibitors of P-gp with IC50 values of 168 μM (95% CI, 118-251 μM) and 204 μM (95% CI, 5.9-1745 μM), respectively. The lack of effect of most of the tested excipients on P-gp transport provides a wide selection of excipients for inclusion in oral formulations with minimal risk of influencing the oral bioavailability of P-gp substrates.

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Acknowledgements

We thank Drs. Per Artutsson and Maria Kalgren for the MDCK-hMDR1-cMDR1-knockout stable cell lines. We also thank Drs. Xiaomin Liang (Gilead Sciences) and Eugene Chen (Genentech) for advice on the digoxin flux assays. Drs. Chenling Xiong, Katherina Chua, Josefina Priotti, and Nura El-Haj provided insightful discussions of the data.

Funding

This research was made possible by Grant U01FD004979/U01FD005978 from the US Food and Drug Administration (FDA), which supports the University of California, San Francisco–Stanford Center of Excellence in Regulatory Sciences and Innovation (UCSF-Stanford CERSI). Funding for the research described in the article was provided by the Office of Generic Drugs through the UCSF–Stanford CERSI. Ruchika Bajaj was partially supported by American Heart Association postdoctoral fellowship Award No. 19POST34370101.

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th Street RH584E, San Francisco, California, 94143-2911, USA

    Ruchika Bajaj, Lisa B Chong, Ling Zou, Kathleen M Giacomini & Deanna L Kroetz

  2. Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

    Eleftheria Tsakalozou & Zhanglin Ni

Authors
  1. Ruchika Bajaj
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  2. Lisa B Chong
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  4. Eleftheria Tsakalozou
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  6. Kathleen M Giacomini
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Contributions

Conceptualization: Ling Zou, Eleftheria Tsakalozou, Zhanglin Ni, Kathleen M. Giacomini, and Deanna L. Kroetz

Investigation: Ruchika Bajaj, Lisa B. Chong, and Ling Zou

Formal analysis: Ruchika Bajaj, Lisa B. Chong, and Ling Zou

Supervision: Kathleen M. Giacomini and Deanna L. Kroetz

Writing original draft: Ruchika Bajaj and Deanna L. Kroetz

Writing, review, and editing: Ruchika Bajaj, Lisa B. Chong, Ling Zou, Eleftheria Tsakalozou, Zhanglin Ni, Kathleen M. Giacomini, and Deanna L. Kroetz

Corresponding author

Correspondence to Deanna L Kroetz.

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Bajaj, R., Chong, L.B., Zou, L. et al. Interaction of Commonly Used Oral Molecular Excipients with P-glycoprotein. AAPS J 23, 106 (2021). https://doi.org/10.1208/s12248-021-00631-8

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