Inhibitory effect of sixteen pharmaceutical excipients on six major organic cation and anion uptake transporters

Abstract

1. To date, relatively little is known about the interactions of pharmaceutical excipients with hepatic and renal drug uptake transporters. The present study was designed to systematically evaluate the effects of 16 commonly consumed excipients on human organic cation transporter 1 and 2 (hOCT1 and hOCT2), human organic anion transporter 1 and 3 (hOAT1 and hOAT3) and human organic anion transporting polypeptide 1B1 and 1B3 (hOATP1B1 and hOATP1B3).

2. The inhibitory effects and mechanisms of excipients on transporters were investigated using in vitro uptake studies, cell viability assays, concentration-dependent studies, and the Lineweaver–Burk plot method.

3. Triton X-100 is a non-competitive inhibitor for all six transporters. Tween 20 inhibits hOCT2, hOAT1, hOAT3, and hOATP1B3 in a mixed way, whereas it competitively inhibits hOATP1B1. The inhibition of Tween 80 is competitive for hOCT2, non-competitive for hOATP1B1 and hOATP1B3, and mixed for hOAT1 and hOAT3. Concentration-dependent studies identify Triton X-100 as a strong inhibitor of hOCT1 and hOCT2 with IC₅₀ values of 20.1 and 4.54 μg/mL, respectively. Additionally, Triton X-100, Tween 20, and Tween 80 strongly inhibit hOAT3 with IC₅₀ values ≤31.0 μg/mL.

4. The present study is significant in understanding the excipient–drug interactions and provides valuable information for excipient selection in drug development.

Keywords:

• Excipients
• drug transporters
• drug–drug interactions
• kidney
• liver

Disclosure statement

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant No. [81673523].