Oral drug delivery utilizing intestinal OATP transporters

Abstract

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 pharmacogenomics 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.

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

“…We and others have already demonstrated that SN-38 is a substrate of OATP1B1 (Nozawa et al, 2005) and OATP1B3 (Yamaguchi et al, 2008), which are clinically important liver-specific uptake transporters. Although OATP2B1 is also expressed in the liver (Tamai et al, 2000), OATP2B1 is likely to be pharmacologically more important in the intestine since OATP2B1, but not OATP1B1 or OATP1B3, is expressed in small-intestinal tissues (Tamai, 2012;Shirasaka et al, 2014). In our previous study, we failed to find a significant increase of SN-38 uptake by OATP2B1-expressing Xenopus oocytes (Nozawa et al, 2005).…”

“…These results suggest that inhibition of OATP2B1 in enterocytes would contribute to effective treatment of SN-38-induced late-onset diarrhea. We next evaluated the effect of fruit juices on OATP2B1-mediated transport of SN-38 since fruit juices interact with OATP2B1 and affect intestinal absorption of substrate drugs (Imanaga et al, 2011;Tamai, 2012;Tamai and Nakanishi, 2013). As shown in Fig.…”

“…Accordingly, both drug transporters and drug-metabolizing enzymes likely contribute to the pharmacologic and toxicologic actions of Another OATP family member, OATP2B1, is expressed in several tissues, including the liver and intestine (Tamai et al, 2000). In the small intestine, OATP2B1 is located at the apical membrane of enterocytes and mediates pH-dependent transport of drugs (Kobayashi et al, 2003;Nozawa et al, 2004;Gröer et al, 2013), contributing to intestinal absorption of drugs (Tamai, 2012). It was reported that the plasma concentration of fexofenadine after oral administration was decreased by coingestion with fruit juices, presumably owing to inhibition of intestinal uptake (Dresser et al, 2002).…”

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

“…We demonstrated that bioavailability of fexofenadine is decreased in individuals with the OATP2B1 c.1457C.T allele and is also decreased in the presence of AJ (Imanaga et al, 2011). These observations imply that AJ interacts with fexofenadine through inhibition of OATP2B1-mediated absorption, although a contribution of OATP1A2 to intestinal AJ-drug interactions cannot be ruled out (Kobayashi et al, 2003;Shirasaka et al, 2010a;Tamai, 2012). Involvement of OATP2B1 in FJdrug interaction was also demonstrated by our recent report describing that coincubation with GFJ, OJ, and AJ significantly inhibited OATP2B1-mediated uptake of estrone-3-sulfate with apparent IC 50 values in the order of GFJ , OJ , AJ (Shirasaka et al, 2013).…”

Investigation of Transport Mechanism of Exendin-4 across Madin Darby Canine Kidney Cell Monolayers

“…31) In addition, organic anion transporting polypeptide (OATP) family, such as OATP1A2 (also named SLCO1A2) and OATP2B1 (also named SLCO2B1), may also contribute to the cellular uptake of exendin-4, which has been reported to mediate intestinal absorption of several drugs. 32) The first step of this study was to demonstrate whether active transport and endocytosis transport is involved in the exendin-4 transport across MDCK cell monolayars. Experimental results of time and concentration effect showed that the cumulative permeation amount of exendin-4 was increased linearly with the concentration or time increasing, and no saturation phenomenon was observed over all time period and concentration range, which were the typical characteristics of passive diffusion.…”