Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

Chetan P. Kulkarni; Jia Yang; Megan L. Koleske; Giovanni Lara; Khondoker Alam; Andre Raw; Bhagwant Rege; Liang Zhao; Dongmei Lu; Lei Zhang; Lawrence X. Yu; Robert A. Lionberger; Kathleen M. Giacomini; Deanna L. Kroetz; Sook Wah Yee

doi:10.3390/pharmaceutics16050647

Pharmaceutics (May 2024)

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

Chetan P. Kulkarni,
Jia Yang,
Megan L. Koleske,
Giovanni Lara,
Khondoker Alam,
Andre Raw,
Bhagwant Rege,
Liang Zhao,
Dongmei Lu,
Lei Zhang,
Lawrence X. Yu,
Robert A. Lionberger,
Kathleen M. Giacomini,
Deanna L. Kroetz,
Sook Wah Yee

Affiliations

Chetan P. Kulkarni: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
Jia Yang: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
Megan L. Koleske: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
Giovanni Lara: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
Khondoker Alam: Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Andre Raw: Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Bhagwant Rege: Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Liang Zhao: Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Dongmei Lu: Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Lei Zhang: Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Lawrence X. Yu: Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Robert A. Lionberger: Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA
Kathleen M. Giacomini: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
Deanna L. Kroetz: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
Sook Wah Yee: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA

DOI: https://doi.org/10.3390/pharmaceutics16050647
Journal volume & issue: Vol. 16, no. 5
p. 647

Abstract

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The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters—OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using 3H-estrone sulfate, 3H-N-methyl quinidine, and 3H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC50 values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC50 values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC50 values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC50 values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants.

Published in Pharmaceutics

ISSN: 1999-4923 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceutics/

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