Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2
Introduction
Impaired glucose-induced insulin secretion and insulin resistance are hallmarks of Type 2 diabetes (noninsulin-dependent diabetes mellitus). To compensate for defective insulin secretion, sulfonylureas have been widely used for more than 40 years in the treatment of Type 2 diabetes. However, there are several disadvantages to sulfonylurea therapy, such as excess hypoglycemia between meals due to the long duration of action of these agents.
Nateglinide (AY4166, Fig. 1) has been exploited as a new class of oral hypoglycemic agent Shinkai et al., 1988, Shinkai et al., 1989. Although the mechanism of insulin secretion induced by nateglinide was the same as that of sulfonylureas Fujitani and Yada, 1994, Akiyoshi et al., 1995, nateglinide exhibited a quicker and shorter lasting hypoglycemic effect than sulfonylureas due to its rapid absorption and elimination Sato et al., 1991, Ikenoue et al., 1997. Because of these pharmacokinetic features, it was suggested that nateglinide could be beneficial in clinical use to prevent postprandial hyperglycemia without causing prolonged hypoglycemia in Type 2 diabetes patients.
Peptide transporters (PEPT1 and PEPT2) mediate the efficient absorption of a wide variety of oral peptide-like drugs in the small intestine and kidney (Inui and Terada, 1999). For example, oral β-lactam antibiotics Saito et al., 1995, Terada et al., 1997a, Terada et al., 1997b, anticancer agent bestatin (Saito et al., 1996) and angiotensine-converting enzyme inhibitors (Boll et al., 1994) are transported by these transporters. Furthermore, intestinal PEPT1 has been utilized to improve the intestinal absorption of poorly absorbed pharmacologically active agents by chemically converting to substrates for PEPT1 Hu et al., 1989, Tsuji et al., 1990, Balimane et al., 1998, Ganapathy et al., 1998, Han et al., 1998, Sawada et al., 1999b. Because these peptide-like drugs are pharmacologically independent each other, the pharmacokinetic profiles and therapeutic efficacy may be affected in coadministration of other peptide-like drugs. Therefore, in order to evaluate the appropriate usage of peptide-like drugs, especially newly developed peptide-like drugs, it should be important to investigate their interaction with peptide transporters.
Nateglinide is a novel oral hypoglycemic agent and a dipeptide-like drug, and therefore, the present study was carried out to examine the interaction of nateglinide with peptide transporters using the human colon adenocarcinoma cell line Caco-2, and rat PEPT1- or rat PEPT2-expressing stable transfectant. Furthermore, the effects of other hypoglycemic agents, sulfonylureas, on peptide transporters were also investigated.
Section snippets
Materials
Nateglinide and [14C]nateglinide (9.00 MBq/mmol) were supplied by Ajinomoto (Yokohama, Japan). [14C]glycylsarcosine (1.78 GBq/mmol) was obtained from Daiichi Pure Chemicals (Ibaraki, Japan), and [3H]alanine (2.07 TBq/mmol) and [3H]threonine (485 GBq/mmol) were from Amersham Int. (Buckinghamshire, UK). Glycylsarcosine, tolbutamide and chlorpropamide were obtained from Sigma (St. Louis, MO). Glibenclamide was purchased from Wako (Kyoto, Japan). All other chemicals used were of the highest purity
Inhibitory effects of nateglinide on glycylsarcosine uptake by peptide transporters
Caco-2 cells have been used as a model for studying the functions of peptide transporters Inui et al., 1992, Saito and Inui, 1993, and it was reported that human PEPT1 was expressed in Caco-2 cells (Liang et al., 1995). First, we examined the effects of nateglinide on [14C]glycylsarcosine uptake by Caco-2 cells and rat PEPT1- or PEPT2-expressing transfectant (LLC-rPEPT1 and LLC-rPEPT2 cells, respectively). As shown in Fig. 2, [14C]glycylsarcosine uptake was not affected in the presence of 0.05
Discussion
The present study have clearly demonstrated that nateglinide have the inhibitory effects on the glycylsarcosine uptake by PEPT1 and PEPT2. The inhibitory effects of this agent on both transporters were characterized as kinetically noncompetitive. Recently, we found that [14C]glycylsarcosine uptake by PEPTs was inhibited by glibenclamide in a noncompetitive fashion, and it was suggested that this agent was bound to a site distinct from the glycylsarcosine binding site (Sawada et al., 1999a). An
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research (B) and a Grant-in-Aid for Scientific Research on Priority Areas (No. 296) from the Ministry of Education, Science, Sports and Culture of Japan, and by grants from the Uehara Memorial Foundation and from the Japan Research Foundation for Clinical Pharmacology.
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2016, Food Research InternationalThe oligopeptide transporter 2-mediated reabsorption of entecavir in rat kidney
2014, European Journal of Pharmaceutical SciencesCitation Excerpt :The proton-coupled oligopeptide transporter 2 (PEPT2) is powered by an inwardly directed proton gradient (Biegel et al., 2006). PEPT2 can mediate the cellular uptake of di/tripeptides and peptidomimetics, such as the endogenous peptidomimetic 5-aminolevulinic acid (Groneberg et al., 2002; Kamal and Smith, 2008), β-lactam antibiotic cefadroxil (Ganapathy et al., 1995), angiotensin-converting enzyme inhibitor fosinopril (Shu et al., 2001), the antiviral agent valganciclovir and the hypoglycemic agent nateglinide (Sugawara et al., 2000; Terada et al., 2000). In kidney, PEPT2 is located in the apical border of proximal tubules (S3 segments) (Shen et al., 1999).
Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H<sup>+</sup> cotransport system in the rat intestinal brush-border membrane
2006, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Since nateglinide is absorbed rapidly from the intestine, it is likely to be absorbed via a specific transporter(s) [2,3]. However, nateglinide is not transported by PEPT1 or MCT1 [8,9]. We have recently shown that nateglinide is absorbed in the intestinal brush-border membrane via the ceftibuten/H+ cotransport system, which is distinct from PepT1, and that the fluorescein/H+ cotransport system is involved in the uptake of nateglinide [12].
Nateglinide uptake by a ceftibuten transporter in the rat kidney brush-border membrane
2005, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :Since nateglinide is absorbed rapidly from the intestine, it is likely to be absorbed via a specific transporter [13,14]. It has been reported that nateglinide itself is not transported by PEPT1 or MCT1 [1,2]. Recently, we reported that nateglinide transport occurs via a single system that may be identical to the ceftibuten/H+ cotransport system by the rat small intestine [3].
Intestinal uptake of nateglinide by an intestinal fluorescein transporter
2005, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :Since nateglinide is absorbed rapidly from the intestine, it is likely to be absorbed via a specific transporter(s) [1–4]. It has been reported that nateglinide is transported in an absorptive direction across Caco-2 cell monolayers, although nateglinide itself is not transported by PEPT1, PEPT2 or MCT1 [5,6]. The transport mechanism of nateglinide in intestinal absorption has not been elucidated yet.