Oral drug delivery utilizing intestinal OATP transporters

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Abstract

Transporters play important roles in tissue distribution and urinary- and biliary-excretion of drugs and transporter molecules involved in those processes have been elucidated well. Furthermore, an involvement of efflux transporters such as P-glycoproteins, multidrug resistance associated protein 2, and breast cancer resistance protein as the intestinal absorption barrier and/or intestinal luminal secretion mechanisms has been demonstrated. However, although there are many suggestions for the contribution of uptake/influx transporters in intestinal absorption of drugs, information on the transporter molecules responsible for the intestinal absorptive process is limited. Among them, most studied absorptive drug transporter is peptide transporter PEPT1. However, utilization of PEPT1 for oral delivery of drugs may not be high due to the chemical structural requirement of PEPT1 limited to peptide-mimetics. Recently, organic anion transporting polypeptide (OATP) family such as OATP1A2 and OATP2B1 has been suggested to mediate intestinal absorption of several drugs. Since OATPs exhibit species difference in expressed tissues and functional properties between human and animals, human studies are essential to clarify the intestinal absorption mechanisms of drugs via OATPs. Recent pharmacogenomic studies demonstrated that OATP2B1 is involved in the drug absorption in human. In addition, information of drug–juice interaction in the intestine also uncovered the contribution of OATP1A2 and OATP2B1 in drug absorption. Since OATP1A2 and OATP2B1 exhibit broader substrate selectivity compared with PEPT1, their potential to be applied for oral delivery should be high. In this review, current understanding of characteristics and contribution as the absorptive transporters of OATPs in small intestine in human is described. Now, it is getting clearer that OATPs have significant roles in intestinal absorption of drugs, therefore, there are higher possibility to utilize OATPs as the tools for oral delivery.

Introduction

An involvement of transporters as the mechanism for intestinal absorption of drugs has been studied during about past five decades. Before molecular cloning of transporter genes, various in vivo and in vitro studies suggested a contribution of the carrier-mediated absorption of drugs via the nutrient transport systems for amino acids, oligopeptides, monocarboxylic acids, water-soluble vitamins, sugars, bile acids, amines, and nucleosides [1], [2]. After molecular cloning of membrane transporter genes in the middle of 1990's, more confirmative evidences which demonstrate the contribution of transporters in drug absorption have been obtained. Peptide transporter PEPT1 (SLC15A1) has been extensively studied as the drug transporter by demonstrating that several clinically used drugs such as beta-lactam antibiotics and valacyclovir are absorbed by PEPT1 due to their structural similarities with native peptides. Since the characteristics of PEPT1 have been clarified well, PEPT1 studies are currently in the stage for utilization of the transporter as the tool for oral delivery by mainly pro-drug approaches [3], [4], [5], [6], [7], [8]. In addition to peptide transporter, we found that certain anion transporters which exhibit pH-dependent transport activity contribute to the absorption/uptake of monocarboxylic acid-type drugs such as benzoic acid [9] and pravastatin [10]. In the beginning, monocarboxylate transporters MCTs (SLC16A family) were hypothesized to contribute as the responsible transporter molecules, since they accept monocarboxylates such as lactic acid and nicotinic acid as substrates. When MCT1 was expressed in Xenopus oocytes or cultured cells, it transported benzoic acid as expected, while pravastatin was not [11], [12]. Therefore, we had to consider that certain other transporters contribute to the absorption of such acidic drugs. Organic anion transport systems in liver and kidney had been studied well and organic anion transporting polypeptide (OATP) was molecularly identified as the anion transporter in liver [13]. Accordingly, we expected that OATP type transporters are expressed and functional as drug absorptive transporter in the small intestine. Since OATPs exhibit significantly broader substrate selectivity than PEPT1, they are more attractive to use as the transporters for oral delivery. In this review, a contribution of OATPs in the intestinal absorption of drugs mainly done by authors is described.

Section snippets

Characteristics of OATP transporter family

Organic anion transporting polypeptides (OATPs, SLCO family) are involved in the cellular uptake of numerous endogenous and xenobiotic organic anions in various tissues and affect absorption and disposition of their substrate drugs. In liver, OATP1B1 (former name is OATP-C), OATP1B3 (OATP8) and OATP2B1 (OATP-B) are expressed at the basolateral membrane of hepatocytes and contribute to hepatic uptake of various compounds [14], [15], while OATP1A2 (OATP-A), which was molecularly identified for

Expression of OATP in enterocytes

Table 1 shows tissue expression profiles of OATPs in human. It is well known that OATP1B1 and OATP1B3 are exclusively expressed in human liver and OATP4C1 is in human kidney [15], [23], [24], [25]. OATP1C1 is in brain and testis and others are expressed multiple tissues, including intestine [15], [26]. Accordingly, other OATPs than OATP1B1, OATP1B3, OATP1C1 and OATP4C1 are possible intestinal OATPs. Since until now drug transports have not been observed well in OATP3A1 and OATP4A1, we focused

In Vitro functional characteristics of OATP2B1

OATP2B1 is characterized by its pH-dependent transport activity. When examined the uptake of estrone-3-sulfate by in vitro OATP2B1-gene transfected cells, it exhibited pH dependent activity [28], [43]. Fig. 3 shows the uptake of estrone-3-sulfate by HEK293 cells transfected with OATP2B1 gene at pH 5.0 and 7.4. OATP2B1 exhibited higher activity at acidic pH and the increase was due to the 7-fold increase of Vmax with only 1.5-fold increase of Km. Although the mechanism of the increase of

Effect of genetic polymorphisms of SLCO2B1

In vivo pharmacological relevance of OATP2B1 is characterized by the effect of genetic polymorphisms of OATP2B1 gene (SLCO2B1). Fig. 4 shows non-synonymous mutations found in genetic variants of SLCO2B1. Among these genetic variants, SLCO2B1*3, which has mutation of c.1457C > T that causes amino acid change of Ser486Phe, exhibited a decreased transport activity by in vitro studies [17]. When SLCO2B1*1 (wild type) and SLCO2B1*3 genes were expressed in vitro cultured cells, uptake activity of

Drug–fruit juice interaction on OATP2B1

Alteration of in vivo drug absorption by concomitantly administered drugs or food/juice provides further evidence for the contribution of transporters in intestinal absorption of drugs. In 2002, significant effect of fruit juices such as grapefruit-, orange- and apple-juices on the plasma concentration of fexofenadine after oral administration was reported [51]. The earlier reports on the increases of bioavailability of drugs by concomitant fruit juice were mainly focused on the interactions of

Perspective of OATP-mediated oral delivery

Tebipenem pivoxyl is a prodrug of carbapenem antibiotic tebipenem and exhibits very high bioavailability by 80% of dose. Since usually observed bioavailability of ester prodrugs is about 30 to 50%, we hypothesized that tebipenem pivoxyl might include carrier-mediated transport in addition to simple diffusion in intestinal membrane permeation [39]. When examined by in vitro studies, tebipenem pivoxyl was shown to be a substrate of OATP1A2 and OATP2B1 but not PEPT1. Although it is not clear

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