Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney

doi:10.1016/S0168-3659(01)00480-1

Journal of Controlled Release

Volume 78, Issues 1–3, 17 January 2002, Pages 43-54

https://doi.org/10.1016/S0168-3659(01)00480-1 Get rights and content

Abstract

Cumulative studies have revealed the importance of transporters in drug disposition in the body. Recently, organic anion transporters such as organic anion transporting polypeptides (OATPs), organic anion transporters (OATs) and multidrug resistance associated proteins (MRPs) have been identified. Their broad substrate specificity as well as the multiplicity of transporter gene products make these transporters suitable detoxification systems in the body. OATPs and OATs are responsible for the hepatic and renal uptake of organic anions, respectively, while MRP2 is a major transporter involved in the biliary excretion of organic anions. OATPs and MRP2 are involved in the hepatobiliary transport of pravastatin and temocaprilat. These are good examples of hepatobiliary transport maximizing their pharmacological effects, but minimizing their side-effects. Taking into consideration tissue-selective expression and substrate specificity, transporters are useful for delivering small molecules to target tissues. MRPs are also suggested to be involved in the barrier function in the small intestine, blood–brain barrier and blood–cerebrospinal fluid barriers by extruding their ligands into the luminal side. In this manuscript, we have summarized recent studies by others and ourselves on the role of these transporters in the tissue selective distribution and elimination of drugs.

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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Citation 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].
Membrane transporters play a key role in the absorption, distribution, clearance, elimination, and transport of drugs. Understanding the drug properties and structure activity relationships (SAR) for affinity to membrane transporters is critical to optimize clearance and pharmacokinetics during drug design. To facilitate the early identification of clearance mechanism, a framework named the extended clearance classification system (ECCS) was recently introduced. Using in vitro and physicochemical properties that are readily available in early drug discovery, ECCS has been successfully applied to identify major clearance mechanism and to implicate the role of membrane transporters in determining pharmacokinetics. While the crystal structures for most of the drug transporters are currently not available, ligand-based modeling approaches that use information obtained from the structure and molecular properties of the ligands have been applied to associate the drug-related properties and transporter-mediated disposition. The approach allows prospective prediction of transporter both substrate and/or inhibitor affinity and build quantitative structure-activity relationship (QSAR) to enable early optimization of pharmacokinetics, tissue distribution and drug-drug interaction risk. Drug design applications can be further improved through uncovering transporter protein crystal structure and generation of quality data to refine and develop viable predictive models.

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Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney

Abstract

Introduction

Section snippets

Drug transporters for organic anions

Role of transporters in the hepatobiliary transport of drugs

Role of MRP2 and MRP3 in the small intestine

Active efflux of anionic drugs through the blood–brain and blood–cerebrospinal fluid barriers

Role of transporters in the renal transport of drugs

Concluding remarks

Acknowledgements

Adv. Drug Deliv. Rev.

Eur. J. Pharm. Sci.

J. Controlled Release

Hepatology

Gastroenterology

J. Hepatol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Gastroenterology

J. Biol. Chem.

Kidney Int.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Biochim. Biophys. Acta

Cancer Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Controlled Release

Eur. J. Pharmacol.

Drug Discov. Today

Drug Discov. Today

Brain Res. Bull.

Biochem. Biophys. Res. Commun.

Brain Res.

Biochem. Biophys. Res. Commun.

Kidney Int.

J. Biol. Chem.

Transporters for bile acids and organic anions

Pharm. Biotechnol.

Transport of drugs across the hepatic sinusoidal membrane: sinusoidal drug influx and efflux in the liver

Semin. Liver Dis.

Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics

Pharm. Res.

Molecular aspects of hepatobiliary transport

Am. J. Physiol.

Uptake of enalapril and expression of organic anion transporting polypeptide 1 in zonal, isolated rat hepatocytes

Drug Metab. Dispos.

Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide

J. Pharmacol. Exp. Ther.

Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane

Hepatology

A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane

Am. J. Physiol.

Hepatic uptake of bilirubin and its conjugates by the human organic anion-transporting polypeptide 2 (symbol SLC21A6)

J. Biol. Chem.

The multispecific organic anion transporter (OAT) family

Pflügers Arch.

Molecular pharmacology of renal organic anion transporters

Am. J. Physiol.

Molecular cloning and characterization of a novel liver-specific transport protein

J. Cell Sci.