Increased protein level of PEPT1 intestinal H⁺-peptide cotransporter upregulates absorption of glycylsarcosine and ceftibuten in 5/6 nephrectomized rats

Abstract

ϩ -coupled peptide transporter (PEPT1/ SLC15A1) plays an important role in the absorption of small peptides and peptide-like drugs in the small intestine. Because dietary protein intake is one of the risk factors for renal failure, the alteration of intestinal PEPT1 might have implications in the progression of renal disease as well as the pharmacokinetics of peptide-like drugs. In this study, we examined the alteration of intestinal PEPT1 in 5/6 nephrectomized (5/6 NR) rats, extensively used as a model of chronic renal failure. Absorption of [14 C]glycylsarcosine and ceftibuten was significantly increased in 5/6 NR rats compared with sham-operated rats, without a change in intestinal protease activity. Western blot analysis indicated that the amount of intestinal PEPT1 protein in 5/6 NR rats was increased mainly at the upper region. On the other hand, the amount of intestinal PEPT1 mRNA was not significantly different from that of sham-operated rats. These findings indicate that the increase in absorption of small peptides and peptide-like drugs, caused by the upregulation of intestinal PEPT1 protein, might contribute to the progression of renal failure as well as the alteration of drug pharmacokinetics. renal failure; H ϩ -coupled peptide transporter; intestine SMALL PEPTIDES, including di-and tripeptides, are the main products of protein digestion in the gut lumen (2, 13). The absorption of small peptides is mediated by H ϩ -coupled peptide transporter (PEPT1), which is localized at the brush-border membranes of intestinal epithelial cells. Furthermore, PEPT1 mediates the absorption of a broad range of peptide-like drugs, such as ␤-lactam antibiotics, the anti-cancer agent bestatin, and angiotensinconverting enzyme (ACE) inhibitors (10, 12, 21). Recently, Gangopadhyay et al. (8) reported that uncontrollable diabetes has a profound effect on the expression of intestinal PEPT1.In chronic renal failure (CRF), morphological and enzymatic abnormalities have been found in the small intestinal mucosa of patients (7) and model rats at 12 wk after nephrectomy (9). For example, the activities of sucrase and maltase were reduced (9), and the expression of intestinal cytochrome P-450 was downregulated in rats at 6 wk after nephrectomy (11). However, the activity of some dipeptidases was significantly but weakly increased or unchanged in the isolated brush-border membranes from the nephrectomized rat intestinal mucosa at 8 wk after surgery (31). It seems plausible to presume that the absorptive function of the mucosa in CRF is disturbed. Recently, the impairment of intestinal P-glycoprotein function was reported in CRF rats (30). In CRF, dietary protein is considered to impair residual renal function, and therefore, patients with CRF are recommended to take a low-protein diet to prevent uremia (25). However, the regulation of intestinal PEPT1 in CRF remains unclear. On the basis of this background, we have hypothesized that the alteration of intestinal PEPT1 has implications not only in the pharmacokinetics of peptide-li...

Intestinal drug transporters in pathological states: an overview

“…Function of Pept1 using its substrates, i.e., [ 14 C]Gly-Sar and ceftibuten, was studied by Shimizu et al [ 27 ] in 5/6 nephrectomized rats. An increased intestinal carrier function associated with significant upregulation of Pept1 protein in the gastrointestinal tract in chronic renal failure animals was found.…”

Role of peptide transporters in small peptide uptake of bovine mammary epithelial cells cultured in a transwell chamber

“…Small peptides can be transported into the bovine mammary gland in intact form by oligopeptide transporters. The known proton‐coupled oligopeptide transporters (POT) include oligopeptide transporter 1 (PepT1), PepT2, small peptide histidine transporter 1 (PhT1), and PhT2, which can transport oligopeptides and peptide analogs to various cells in reverse concentrations driven by electron gradients (Fowler et al, 2015 ; Smith et al, 2013 ; Verri et al, 2017 ); they play important physiological roles in animal growth and metabolism (Alghamdi et al, 2019 ; Shimizu et al, 2004 ). Currently, research on POT mainly focuses on intestinal small peptide absorption and renal tubular reabsorption, as well as drug transport in the animal body (Daniel, 2004 ; Newstead, 2017 ; Oppermann et al, 2019 ).…”