Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney
Introduction
Cumulative in vivo and in vitro studies indicate that transporters are one of the determinant factors governing drug disposition, and multispecific transporters are involved in hepatobiliary and urinary excretion. Generally, amphipathic organic anions with relatively high molecular weight are eliminated from the liver by metabolism and/or biliary excretion, while small and hydrophilic organic anions are excreted into the urine. Recently, many types of transporters have been isolated from animals and human (Fig. 1), and their substrate specificity has been characterized using cRNA-injected oocytes and cDNA-transfected cells. Tissue distribution and elimination pathways of drugs are being explained by the similarity and differences in the substrate recognition by transporters expressed in the liver and kidney. In this manuscript, the recent progress made in our own laboratory and by others will be summarized, focusing particularly on the role of transporters in drug disposition using isolated cells, plasma membrane vesicles and/or cDNA transfected cells. The role of transporters in drug disposition has also been summarized in other review articles [1], [2], [3], [4], [5], [6].
Section snippets
Drug transporters for organic anions
In this section, transporters involved in the disposition of drugs, especially drugs with an anionic moiety, are briefly described below.
Role of transporters in the hepatobiliary transport of drugs
Pravastatin is a typical case of a carrier-mediated active transport system which contributes to its liver-specific distribution in the body [6]. The hepatic uptake clearance of pravastatin determined in vivo by integration plot analysis was comparable with the blood-flow rate, suggesting high-extraction in the liver during a single pass [6]. Since the pharmacological target of pravastatin is the liver, such efficient uptake system is beneficial from a pharmacological point of view. According
Role of MRP2 and MRP3 in the small intestine
Since both MRP2 and MRP3 are also expressed in the small intestine, these transporters may play some functional role. The functional role of MRP2 in the small intestinal secretion of anionic compounds was examined by comparing normal rats and EHBR. The intestinal excretion clearance of DNP-SG, determined using an everted sac prepared from the jejunum, was markedly reduced in EHBR. That prepared from the duodenum was 2-fold higher in normal rats although the difference was not statistically
Active efflux of anionic drugs through the blood–brain and blood–cerebrospinal fluid barriers
Both brain capillary endothelial cells and the choroid plexus (a tiny tissue located in the ventricle) act as barriers against xenobiotics in the circulating blood and, thus are referred to as the blood–brain barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB), respectively. Cumulative studies revealed that efficient efflux transport systems are located on the BBB and BCSFB (Fig. 3) [1], [5], [57], [58], [59], [60].
We have characterized the efflux of organic anions, such as taurocholate
Role of transporters in the renal transport of drugs
There is an efficient uptake system for PAH in the kidney. Trans-stimulation by dicarboxylate is a typical feature for the renal uptake of PAH which is consistent with the transport character of rOat1 [21], [22], [23]. rOat1 is considered to be responsible for the renal uptake of PAH [21], [22], [23] (Fig. 1). Northern blot analysis indicates the expression of rOat3 in the kidney [27], although the role of rOat3 in the renal uptake of organic anions remains to be clarified.
The uptake clearance
Concluding remarks
Due to the broad substrate specificity of drug transporters, drug–drug interactions on the transporters is very likely. It is necessary to screen therapeutic agents to identify those with a lower chance of such drug–drug interactions. In that sense, in vitro systems, such as cDNA-transfected cells, appear to be efficient tools for screening of drugs in terms of their inhibitory activity on such transporters, as recombinant enzymes, such as CYP isozyme expression systems, have been widely used
Acknowledgements
This work was supported by CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation.
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2017, Advanced Drug Delivery ReviewsCitation Excerpt :It pumps endogenous metabolites, such as conjugated bilirubin and bile salts, into bile [88,89]. MRP2 also transport anionic conjugates of drugs [90,91] and many structurally diverse xenobiotics and their metabolites as part of the hepatic detoxification process [92–96]. MRP2 was proposed to possess two distinct binding sites: one site for substrate transport and a second site that allosterically regulates the affinity of the transport site for the substrate [97].