Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V max for OATP1B1-mediated transport of E 2 17b-G (estradiol 17b-D-glucuronide) was decreased >60%, whereas K m values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K m 13.1 6 0.43 mM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC 50 values for inhibition of E 2 17b-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients.

The majority of intestinal in vitro screening models use cell lines that do not reflect the complexity of the human intestinal tract and hence often fail to accurately predict intestinal...

Colon microbiota-based drug metabolism has received little attention thus far in the process of drug development, whereas the role of gut microbiota in clinical safety and efficacy of drugs has become more clear. Many of these studies have been performed using animal studies, but the translational value of these data with respect to drug pharmacokinetics, efficacy, and safety is largely unknown. To investigate human colon microbiota-mediated drug metabolism, we applied a recently developed ex vivo fermentation screening platform, in which human colonic microbiota conditions are simulated. A set of 12 drugs (omeprazole, simvastatin, metronidazole, risperidone, sulfinpyrazone, sulindac, levodopa, dapsone, nizatidine, sulfasalazine, zonisamide, and acetaminophen) was incubated with human colon microbiota under strictly anaerobic conditions, and samples were analyzed using high-performance liquid chromatograph-UV-high-resolution mass spectrometry analysis. The human microbiota in the fermentation assay consisted of bacterial genera regularly encountered in human colon and fecal samples and could be reproducibly cultured in independent experiments over time. In addition, fully anaerobic culture conditions could be maintained for 24 hours of incubation. Five out of the 12 included drugs (sulfasalazine, sulfinpyrazone, sulindac, nizatidine, and risperidone) showed microbiota-based biotransformation after 24 hours of incubation in the ex vivo fermentation assay. We demonstrated that drug metabolites formed by microbial metabolism can be detected in a qualitative manner and that the data are in accordance with those reported earlier for in vivo metabolism. In conclusion, we present a research tool to investigate human colon microbiota-based drug metabolism that may be applied to enable translatability of microbiota-based drug metabolism.