Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H+ cotransport system in the rat intestinal brush-border membrane

Saito, Yoshitaka; Itagaki, Shirou; Kubo, Sachiko; Kobayashi, Masaki; Hirano, Takeshi; Iseki, Ken

doi:10.1016/j.bbrc.2005.12.092

Cited by 3 publications

(1 citation statement)

References 22 publications

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“…In rat intestinal brush-border vesicles, it has been shown that the ceftibuten/H + cotransport system, which is identical to the fluorescein/H + cotransport system, is involved in the uptake of nateglinide (Itagaki et al, 2005b;Saito et al, 2006). Furthermore, nateglinide inhibits rat peptide transporters 1 and 2, rat organic anion transporter, and human MCT1, but is not transported by these transporters (Terada et al, 2000;Uwai et al, 2000;Okamura et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Monocarboxylate Transporter 6: Expression in Human Intestine and Transport of the Antidiabetic Drug Nateglinide

Kohyama¹,

Shiokawa²,

Ohbayashi³

et al. 2013

Drug Metab Dispos

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Monocarboxylate transporter (MCT) 6, encoded by SLC16A5, is a member of the monocarboxylate transporter family. Nateglinide, an oral hypoglycemic agent, quickly reaches the maximal serum concentration after its premeal administration. Although the functional existence of uptake systems for nateglinide in the intestine has been demonstrated, these transport systems have not yet been identified at the molecular level. The aim of this study was to demonstrate the localization of MCT6 in the human small intestine and characterize the transport properties of nateglinide via MCT6. Immunohistochemical analysis of the human small intestine revealed that anti-MCT6 antiserum stained the luminal side of the epithelial cells. When expressed in Xenopus laevis oocytes, MCT6-mediated uptake of [ 14 C]nateglinide was sensitive to extracellular pH and membrane potential. Furthermore, the K t value of nateglinide (45.9 mM) for MCT6 was lower than those previously reported in Caco-2 cells and rat intestinal brush-border membrane vesicles. In addition, probenecid, fluorescein, valproic acid, and salicylic acid, which are inhibitors of nateglinide uptake in Caco-2 cells and rat intestine, did not inhibit the uptake of nateglinide via MCT6. These results suggest that MCT6 may play a role in the intestinal absorption of nateglinide, although other transporters are also likely involved.

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Section: Introductionmentioning

confidence: 99%

Characterization of Monocarboxylate Transporter 6: Expression in Human Intestine and Transport of the Antidiabetic Drug Nateglinide

Kohyama¹,

Shiokawa²,

Ohbayashi³

et al. 2013

Drug Metab Dispos

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Intestinal Absorption and Secretion Mechanism of Carboxylate Drugs

Itagaki

2009

YAKUGAKU ZASSHI

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Oral drug delivery is generally the most desirable means of administration, mainly because of patient acceptance, convenience in administration. Intestinal absorption mechanisms of anionic drugs have been mainly explained by the passive diŠusion of nonionized compounds. However, several studies have suggested the involvement of speciˆc transporters in intestinal absorption of weak acids including monocarboxylates. (-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a oral hypoglycemic agent possessing a carboxyl group and a peptide-type bond in its structure. Although nateglinide quickly reaches the maximal serum concentration after oral administration, nateglinide itself is not transported by PepT1 or MCT1. We demonstrated that nateglinide transport occurs via a single system that is H ＋ dependent but is distinct from PepT1 or MCT1. In clinical, patients usually take many kinds of drugs at the same time. Thus, drug-drug interactions involving transporters can often directly aŠect the therapeutic safety and e‹cacy of many drugs. However, there have been few studies on food-drug interactions involving transporters. Dietary polyphenols have been widely assumed to be beneˆcial to human health. Polyphenols are commercially prepared and used as functional foods. We reported that ferulic acid, which is widely used as a functional food, aŠects the transport of clinical agents. The major dose-limiting toxicity after administration of irinotecan hydrochloride, 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxycamptothecin (CPT-11) is severe diarrhea. We have found that a speciˆc transport system mediates the uptake of active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) across the apical membrane in Caco-2 cells. Baicalin and sulfobromophthatlein inhibit this transporter. Inhibition of this transporter would be a useful means for reducing late-onset diarrhea.

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Drug-Drug and Food-Drug Pharmacokinetic Interactions with New Insulinotropic Agents Repaglinide and Nateglinide

Scheen

2007

Clinical Pharmacokinetics

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This review describes the current knowledge on drug-drug and food-drug interactions with repaglinide and nateglinide. These two meglitinide derivatives, commonly called glinides, have been developed for improving insulin secretion of patients with type 2 diabetes mellitus. They are increasingly used either in monotherapy or in combination with other oral antihyperglycaemic agents for the treatment of type 2 diabetes. Compared with sulfonylureas, glinides have been shown to (i) provide a better control of postprandial hyperglycaemia, (ii) overcome some adverse effects, such as hypoglycaemia, and (iii) have a more favourable safety profile, especially in patients with renal failure. The meal-related timing of administration of glinides and the potential influence of food and meal composition on their bioavailability may be important. In addition, some food components (e.g. grapefruit juice) may cause pharmacokinetic interactions. Because glinides are metabolised via cytochrome P450 (CYP) 3A4 isoenzyme, they are indeed exposed to pharmacokinetic interactions. In addition to CYP3A4, repaglinide is metabolised via CYP2C8, while nateglinide metabolism also involves CYP2C9. Furthermore, both compounds and their metabolites may undergo specialised transport/uptake in the intestine, another source of pharmacokinetic interactions. Clinically relevant drug-drug interactions are those that occur when glinides are administered together with other glucose-lowering agents or compounds widely coadministered to diabetic patients (e.g. lipid-lowering agents), with drugs that are known to induce (risk of lower glinide plasma levels and thus of deterioration of glucose control) or inhibit (risk of higher glinide plasma levels leading to hypoglycaemia) CYP isoenzymes concerned in their metabolism, or with drugs that have a narrow efficacy : toxicity ratio. Pharmacokinetic interactions reported in the literature appear to be more frequent and more important with repaglinide than with nateglinide. Rifampicin (rifampin) reduced repaglinide area under the plasma concentration-time curve (AUC) by 32-85% while it reduced nateglinide AUC by almost 25%. Reported increases in AUCs with coadministration of drugs inhibiting CYP isoenzymes never exceeded 80% for repaglinide (except with ciclosporin and with gemfibrozil) and 50% for nateglinide. Ciclosporin more than doubled repaglinide AUC (+144%), a finding that should raise caution when using these two drugs in combination. The most impressive pharmacokinetic interaction was reported with combined administration of gemfibrozil (a strong CYP2C8 inhibitor) and repaglinide (8-fold increase in repaglinide AUC). Although no studies have been performed in patients with type 2 diabetes, the latter combination should be avoided in clinical practice.

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Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H+ cotransport system in the rat intestinal brush-border membrane

Cited by 3 publications

References 22 publications

Characterization of Monocarboxylate Transporter 6: Expression in Human Intestine and Transport of the Antidiabetic Drug Nateglinide

Characterization of Monocarboxylate Transporter 6: Expression in Human Intestine and Transport of the Antidiabetic Drug Nateglinide

Intestinal Absorption and Secretion Mechanism of Carboxylate Drugs

Drug-Drug and Food-Drug Pharmacokinetic Interactions with New Insulinotropic Agents Repaglinide and Nateglinide

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