Food Additives as Inhibitors of Intestinal Drug Transporter OATP2B1

Abstract

Food additives are compounds that are added to food and beverage to improve taste, color, preservation or composition. Generally, food additives are considered safe for human use due to safety evaluation conducted by food safety authorities and high safety margins applied to permitted usage levels. However, the interaction potential of food additives with simultaneously administered medication has not received much attention. Even though many food additives are poorly absorbed into systemic circulation, high concentrations could exist in the intestinal lumen making intestinal drug transporters, such as the uptake transporter organic anion transporting polypeptide 2B1 (OATP2B1), a possible site of food additive-drug interaction. In the present work, we aimed to characterize the interaction of a selection of 25 food additives including colorants, preservatives and sweeteners with OATP2B1 in vitro. In HEK293 cells transiently overexpressing OATP2B1 or control, uptake of dibromofluorescein was studied with and without 50 µM food additive at pH 7.4. As OATP2B1 displays substrateand pH-dependent transport function and the intraluminal pH varies along the gastrointestinal tract, we performed the studies also at pH 5.5 using estrone sulfate as OATP2B1 substrate. Food additives that inhibited OATP2B1mediated substrate transport with ≥50% were subjected to dose-response studies. Six colorants were identified and validated as OATP2B1 inhibitors at pH 5.5, but only three of these were categorized as inhibitors at pH 7.4. One sweetener was validated as an inhibitor at both assay conditions whereas none of the preservatives exhibited ≥50% inhibition of OATP2B1-mediated transport. Extrapolation of computed inhibitory constants (Ki values) to estimations of intestinal food additive concentrations imply that selected colorants could inhibit intestinal OATP2B1 also in vivo. These results suggest that food additives, especially colorants, could alter the pharmacokinetics of orally administered OATP2B1 substrate drugs, although further in vivo studies are warranted to understand the overall clinical consequences of the findings.

Functional Characterization of Six SLCO1B1 (OATP1B1) Variants Observed in Finnish Individuals with a Psychotic Disorder

“…GATC Biotech’s (Constance, Germany) sequencing service confirmed the presence of the SNVs in the plasmids. Baculoviruses carrying the reference SLCO1B1 gene, the variant SLCO1B1 genes, and the previously cloned gene for enhanced yellow fluorescent protein (eYFP) as a negative control were produced as described earlier by Tikkanen et al…”

“…GATC Biotech's (Constance, Germany) sequencing service confirmed the presence of the SNVs in the plasmids. Baculoviruses carrying the reference SLCO1B1 gene, the variant SLCO1B1 genes, and the previously cloned gene for enhanced yellow fluorescent protein (eYFP) as a negative control were produced as described earlier by Tikkanen et al 28 Cell Culture and Protein Expression. HEK293 human kidney cells were cultured in Dulbecco's modified Eagle medium (DMEM) and high-glucose GlutaMax culture medium supplemented with 10% fetal bovine serum (FBS) at 37 °C, 5% CO 2 .…”

Functional characterization of six SLCO1B1 (OATP1B1) variants observed in Finnish individuals with a psychotic disorder

“…GATC Biotech’s (Constance, Germany) sequencing service confirmed the presence of the SNVs in the plasmids. Baculoviruses carrying the reference SLCO1B1 gene, the variant SLCO1B1 genes and the previously cloned gene for enhanced yellow fluorescent protein (eYFP) as a negative control were produced as described earlier by Tikkanen et al 28 .…”

Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs)

“…Avicularin has also been reported to inhibit OATP2B1, which in turn, does not have selective inhibitors. However, many drugs and food additives have been reported to interfere with OATP2B1 function [211,212]. Therefore, both OATP1A2 and 2B1 are susceptible to drug-drug and drug-food interactions, already in the gastrointestinal tract, exemplified by well-known interactions with statins, fexofenadine (antihistamine), and aliskiren (renin inhibitor, used in the treatment of hypertension) [213,214].…”