Pharmaceutical excipients influence the function of human uptake transporting proteins

Area of Science:

• Pharmacology
• Drug Metabolism and Transporter Interactions

Background:

• Pharmaceutical excipients are generally considered inactive, but some solubilizing agents interact with drug metabolism enzymes (CYP) and efflux transporters (P-gp, MRP2).
• Limited data exists on the impact of excipients on drug uptake transporters, which are crucial for drug disposition.

Purpose of the Study:

• To investigate the in vitro effects of polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol HS 15 (SOL), and Cremophor EL (CrEL) on key drug uptake transporters.
• Specifically, to assess their influence on organic anion transporting polypeptides (OATP1A2, OATP2B1, OATP1B1, OATP1B3) and Na+/taurocholate cotransporting polypeptide (NTCP).

Main Methods:

• Utilized stably transfected human embryonic kidney cells expressing specific uptake transporters.
• Assessed excipient inhibition by measuring the uptake of model substrates like bromosulfophthalein, estrone-3-sulfate (E3S), estradiol-17β-glucuronide, and taurocholate (TA).

Main Results:

• Solutol HS 15 (SOL) and Cremophor EL (CrEL) were potent inhibitors of all tested transporters, especially OATP1A2, OATP1B3, and OATP2B1 (IC50 < 0.01%).
• Hydroxypropyl-β-cyclodextrin (HPCD) strongly inhibited transporters for sterane-backbone substrates.
• Polyethylene glycol 400 (PEG) selectively and potently modulated OATP1A2 (IC50 values of 0.05% for TA and 0.14% for E3S).

Conclusions:

• Frequently used solubilizing agents significantly interact with intestinal and hepatic uptake transporters.
• These interactions represent a critical consideration during drug development.
• Further in vivo studies are necessary to determine the clinical relevance of these in vitro findings.