Contrast-enhancing magnetic resonance imaging with the liver-specific agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) has been shown to improve the detection rate of focal lesions. There is evidence from preclinical studies that multidrug organic anion transporters are involved in hepatic uptake of Gd-EOB-DTPA. Therefore, we evaluated affinity of the contrast agent to human organic anion-transporting polypeptides (OATP1B1, OATP1B3, OATP2B1) and to the Na⁺/taurocholate cotransporting polypeptide (NTCP) using stable transfected human embryonic kidney (HEK) 293 cells. In competition assays, Gd-EOB-DTPA inhibited the uptake of bromosulfophthalein (BSP) by OATP1B1 (IC₅₀ = 0.6 mM) and OATP1B3 (IC₅₀ = 0.4 mM). In comparison, the IC₅₀ values for rifampicin were 11.9 (OATP1B1), 1.4 (OATP1B3), and 80.5 μM (OATP2B1), respectively. Uptake of BSP by OATP2B1, uptake of taurocholic acid by NTCP, and viability of all HEK cells were not influenced by Gd-EOB-DTPA in concentrations up to 10 mM. In uptake assays using a new liquid chromatography-tandem mass spectrometry method for quantification, Gd-EOB-DTPA was a substrate for OATP1B1 (K_m = 0.7 mM, V_max = 10.5 pmol/mg × min), OATP1B3 (K_m = 4.1 mM, V_max = 22.7 pmol/mg × min), and NTCP (K_m = 0.04 mM, V_max = 1.4 pmol/mg × min). The uptake by OATP2B1 was not different from the vector control. In conclusion, Gd-EOB-DTPA is a substrate of the liver-specific OATP1B1, OATP1B3, and NTCP.

The liver-specific human organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are uptake carriers for gadoxetic acid, the activity of which may be used to predict the signal intensity in gadoxetic acid-enhanced liver MR imaging. PurposeTo determine if genetic polymorphisms of liver-specific human organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 influence cellular uptake of gadoxetic acid in vitro and if functionally relevant polymorphisms are confounders for liver enhancement by gadoxetic acid in healthy subjects.Materials and MethodsThis study received ethics approval, and all subjects provided written informed consent. Cellular uptake of gadoxetic acid by OATP1B1 and OATP1B3 and their frequent genetic variants was measured by using stable transfected embryonic kidney HEK293 cells. Liver signal intensity at gadoxetic acid–enhanced MR imaging and pharmacokinetics of gadoxetic acid were evaluated in 36 healthy carriers of SLCO1B1/1B3 wild-type alleles (n = 10), SLCO1B1*1b/*1b (n = 8), SLCO1B1*15/*15 (n = 7), SLCO1B1*5/*15 (n = 1), SLCO1B1*1a/*5 (n = 6), and SLCO1B3*4/*4 (n = 4) by using T1-weighted MR imaging and liquid chromatography tandem mass spectrometry.ResultsTransport activity for gadoxetic acid was increased ...

Although oral drug administration is currently the favorable route of administration, intestinal drug absorption is challenged by several highly variable and poorly predictable processes such as gastrointestinal motility, intestinal drug solubility and intestinal metabolism. One further determinant identified and characterized during the last two decades is the intestinal drug transport that is mediated by several transmembrane proteins such as P-gp, BCRP, PEPT1 and OATP2B1. It is well-established that intestinal transporters can affect oral absorption of many drugs in a significant manner either by facilitating their cellular uptake or by pumping them back to gut lumen, which limits their oral bioavailability. Their functional relevance becomes even more apparent in cases of unwanted drug-drug interactions when concomitantly given drugs that cause transporter induction or inhibition, which in turn leads to increased or decreased drug exposure. The longitudinal expression of several intestinal transporters is not homogeneous along the human intestine, which may have functional implications on the preferable site of intestinal drug absorption. Besides the knowledge about the expression of pharmacologically relevant transporters in human intestinal tissue, their exact localization on the apical or basolateral membrane of enterocytes is also of interest but in several cases debatable. Finally, there is obviously a coordinative interplay of intestinal transporters (apical–basolateral), intestinal enzymes and transporters as well as intestinal and hepatic transporters. This review aims to give an updated overview about the expression, localization, regulation and function of clinically relevant transporter proteins in the human intestine.