Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats

The role of intestinal efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in intestinal absorption of methotrexate was examined in rats. In everted intestine, the mucosal efflux of methotrexate after application to serosal side was higher in jejunum than ileum, and the efflux in jejunum was suppressed by pantoprazole, a BCRP inhibitor, and probenecid, an MRP inhibitor, but not by verapamil, a P-gp inhibitor. The mucosal methotrexate efflux in ileum was suppressed by pantoprazole, but not by other inhibitors. On the other hand, the serosal efflux of methotrexate after application to mucosal side was greater in ileum than jejunum, and was suppressed by probenecid. In in-vivo rat studies, the intestinal absorption of methotrexate was significantly higher when methotrexate was administered to ileum than jejunum. Pantoprazole increased methotrexate absorption from jejunum and ileum. Probenecid increased the absorption of methotrexate from jejunum but decreased the absorption from ileum, as evaluated by peak plasma methotrexate levels. In conclusion, BCRP and MRPs are involved in the regional difference in absorption of methotrexate along the intestine, depending on their expression sites.     

Effect of indomethacin on glucose absorption and insulin release in patients with impaired glucose tolerance

Determinations of the levels of blood glucose and of serum insulin-like activity were made in 12 patients with impaired glucose absorption treated with indomethacin 4 x 25 mg for a day. By comparing the results with untreated control patients, it was found that the peak blood level of glucose, and the serum level of insulin-like activity, could be significantly decreased by this oral administration of indomethacin. The decrease of blood level of glucose appeared 0.5 h before the decrease of insulin-like activity in these patients with impaired glucose tolerance.     

The influence of diphenylhydantoin on intestinal glucose absorption in the rat

The influence of diphenylhydantoin (DPH) on intestinal glucose absoprtion was studied by perfusing an isolated jejunal loop of a rat under urethane anaesthesia. DPH produced dose dependent enhancement of glucose absorption. Since DPH also stimulates the absorption of 3-O-methylglucose, but not fructose, the stimulatory effect was considered to be primarily on facilitated transport.The highest concentration of DPH in the perfusate (10^{-4 M})stimulated the appearance of sodium in an originally sodium-free perfusate, while ouabain (1.25 mg/kg body wieght, i.v.) diminished this process. On the basis of these results an additional sodium pump, directed towards the lumen, is postulated in the brush border of the intestinal epithelial cell. The discrepancy between the results of in vitro experiments concerning the influence of sodium ions on intestinal glucose absorption, and the possible physiological role of the proposed apical sodium pump are discussed.     

Cytochalasin E: Inhibition of intestinal glucose absorption in the mouse

In situ glucose absorption in the mouse was significantly inhibited by cytochalasin E. Cytochalasin E (5 mg/ml) also inhibited glucose absorption up to 55.5% in mouse jejunum in vitro. During its inhibition transmural potential difference (PD) was increased from −7.4 to −0.4 mV, together with a decrease in glucose accumulation in the intestinal tissues. Furthermore, it was also found that cytochalasin E induced an alteration in K_m value from 2.9 · 10⁻³ to 4.0 · 10⁻² M and a constant V_max value of 55.5 smmol/100 mg wet wt tissue/min. It is postulated that cytochalasin E is a possible competitive inhibitor of glucose at the receptor sites of carriers on the microvillar membrane of the intestinal absorptive cells.     

Role of glucose transporters in the intestinal absorption of gastrodin,a highly water-soluble drug with good oral bioavailability

Abstract

Gastrodin, a sedative drug, is a highly water-soluble phenolic glucoside with poor liposolubility but exhibits good oral bioavailability. The current study aims to investigate whether glucose transporters (GLTs) are involved in the intestinal absorption of gastrodin. The intestinal absorption kinetics of gastrodin was determined using the rat everted gut sac model, the Caco-2 cell culture model and the perfused rat intestinal model. In vivo pharmacokinetic studies using diabetic rats with high GLT expression were performed. Saturable intestinal absorption of gastrodin was observed in rat everted gut sacs. The apparent permeability (Papp) of gastrodin from the apical (A) to basolateral (B) side in Caco-2 cells was two-fold higher than that from B to A. Glucose or phlorizin, a sodium-dependent GLT (SGLT) inhibitor, reduced the absorption rates of gastrodin from perfused rat intestines. In vivo pharmacokinetic studies showed that the time of maximum plasma gastrodin concentration (T_max) was prolonged from 28 to 72?min when orally co-administered with four times higher dose of glucose. However, the T_max of gastrodin in diabetic rats was significantly lowered to 20?min because of the high intestinal SGLT1 level. In conclusion, our findings indicate that SGLT1 can facilitate the intestinal absorption of gastrodin.     

Inhibition of intestinal glucose absorption in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Male Sprague-Dawley rats were injected with either 125 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg or vehicle (pair-fed and ad libitum-fed controls). Transfer of water, electrolytes and D-glucose as well as fats of a tracer dose of the non-metabolizable radioactive marker 3-O-methyl-D-[U-14C]glucose was studied in isolated perfused jejunal segments 1, 2, 7, and 21 d after treatment (TCDD-treated and pair-fed control rats) and after 26 d in ad libitum-fed controls. TCDD-treated rats demonstrated reduced feed consumption and loss of body weight. Active intestinal absorption of glucose was significantly inhibited 30 and 22% compared to pair-fed controls, respectively 2 and 7 d after TCDD treatment. After 21 d the inhibition (14%) was less significant. There were no differences in glucose transfer between severely starved pair-fed controls (body weights 370 +/- 26 g) and ad libitum-fed rats (body weights 512 +/- 15 g). Water absorption and transfer of sodium and calcium was not influenced by TCDD treatment. However, a significant increase of potassium transfer was observed in parallel with impaired glucose absorption. The uptake of 3-O-methylglucose into mucosal tissue was not impaired, whereas the transfer to the serosal side was significantly inhibited by 30-60% compared to pair-fed as well as ad libitum-fed animals from day 2 until the end of the experiment. These results suggest that TCDD is involved in an inhibition of glucose transport at the basolateral membrane.     

Reconsideration of inhibitory effect of metformin on intestinal glucose absorption.

New evidence that metformin increases intestinal glucose metabolism has necessitated a re-examination of the effect of metformin on intestinal glucose absorption. Normal 18 h fasted mice received an intragastric bolus of metformin 2 h before preparation of everted gut sacs from the proximal, middle and distal regions of the jejunum and ileum. Net mucosal glucose transfer from the intestinal lumen into the tissue was reduced by 15 and 28% after 50 and 250 mg kg-1 metformin, respectively (ANOVA, P less than 0.05). Net glucose transfer into the serosal fluid was reduced by 12 and 70% after 50 and 250 mg kg-1 metformin respectively (ANOVA, P less than 0.05 and P less than 0.01). The inhibitory effect of metformin on both the mucosal and serosal glucose transfer mechanisms was greatest in the middle portion of the small intestine. The results suggest that metformin decreases intestinal glucose absorption in a dose-dependent manner by effects on mucosal and serosal glucose transfer.     

Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine

To investigate the effect of metformin on intestinal glucose absorption, a perfusion study of the intestine was performed in the rat. Male Wistar albino rats (8 weeks old) were used in the present study. The glucose absorption by the perfused intestine (788.1+/-81.9 micromol/30 min) was not changed significantly by the direct addition of metformin (90 microg/mL) to the perfusing medium (737.0+/-118.2 micromol/30 min) or by intraduodenal metformin (250 mg/kg in saline solution) infusion (772.8+/-106.3 micromol/30 min). In rats orally administered metformin (250 mg/kg) for 5 days, glucose absorption by the perfused intestine (375.0+/-164.3 micromol/30 min) was significantly (P<0.001) lower than that in control rats (811.0+/-83.1 micromol/30 min). These results indicate that metformin had a significant effect on the digestive tract, and that metformin treatment exerted an inhibitory effect on intestinal glucose absorption in the rat.     

Role of intestinal metallothionein in absorption and distribution of orally administered cadmium

The effects of mucosal metallothionein (MT) preinduced by Zn on the intestinal absorption and tissue distribution of Cd were studied. 109CdCl2 was administered to control and Zn-pretreated rats. The total amount of Cd distributed to the liver and the kidney in the group pretreated with 100 mg/kg of Zn was about 70% that of the control group. In the control group, the Cd concentration in the intestinal mucosa reached a maximum 16-24 hr after its administration and then gradually decreased with time, unlike that in the liver and the kidney. The concentration of intestinal Cd in the pretreated group reached a maximum earlier than it did in the control group and most of the Cd was in the MT fraction. Pretreatment with Zn (100 mg/kg or higher, po) caused a reduction in the Cd concentration in the liver and an increase in the kidney. Pretreatment with Zn (5 X 10 mg/kg, sc) or Cd (5 mg/kg, po) also increased renal Cd concentration. This was effective at 24 hr but not at 0.5 hr after pretreatment. These effects of pretreatment with Zn (100 mg/kg, po) on tissue distribution of Cd were also observed after an intraintestinal injection of Cd but not after an iv injection. The results indicate that MT in intestinal mucosa plays a significant role not only in the absorption of Cd but also in its transport to the kidney.     

Chronic acarbose-feeding increases GLUT1 protein without changing intestinal glucose absorption function.

As alpha-glucosidase inhibitor, the antidiabetic drug acarbose reduces postprandial glucose levels by retarding the intestinal digestion of polysaccharides. However, it is unknown if acarbose also affects the expression of intestinal glucose transporters, especially the Na(+)-glucose cotransporter (SGLT1) and the glucose transporters GLUT1 and GLUT2. To unravel this question, Wistar rats received standard powdered chow either without (control) or with acarbose (40 mg acarbose/100 g chow) for 40 days. While food intake was slightly enhanced by acarbose, the drug had no influence on weight gain or plasma glucose and insulin levels. The acarbose-treatment did not alter the SGLT1 and GLUT2 gene expression in both upper and middle small intestine, whereas GLUT1 protein was increased by 75% in middle small intestine. Despite the territorial change in GLUT1 protein, the intestinal glucose absorption in an acarbose-free perfusion study was unaltered. In conclusion, the chronic use of acarbose did not alter the acarbose-free glucose absorption profile.     

Pharmacogenetics of intestinal absorption

The small intestine is the primary site of absorption for many drugs administered orally and so is the target tissue for pharmacotherapeutic strategies to control the oral absorption of drugs. Drug transporters, including the ATP-binding cassette (ABC) superfamily and the solute carrier (SLC) superfamily, have been considered to play a physiological role in regulating the absorption of xenobiotics, and variations in their expression level and function in the small intestine cause intra- and inter-individual variation in the oral absorption of drugs. Recent advances in molecular biology have suggested that genetic polymorphisms are associated with the expression level and function, and thereby inter-individual variation. In this review, the pharmacogenetics of these transporters is summarized, and their future significance in the clinical setting is discussed.