Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

• Main Authors: Chetan P. Kulkarni (Author), Jia Yang (Author), Megan L. Koleske (Author), Giovanni Lara (Author), Khondoker Alam (Author), Andre Raw (Author), Bhagwant Rege (Author), Liang Zhao (Author), Dongmei Lu (Author), Lei Zhang (Author), Lawrence X. Yu (Author), Robert A. Lionberger (Author), Kathleen M. Giacomini (Author), Deanna L. Kroetz (Author), Sook Wah Yee (Author)
• Format: Book
• Published: MDPI AG, 2024-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

10.3390/pharmaceutics16050647
1999-4923