Quantitative contributions of hepatic and renal organic cation transporters to the clinical pharmacokinetic cimetidine-metformin interaction.

The widely prescribed oral anti-diabetic drug metformin is eliminated unchanged in the urine primarily through active tubular secretion. This process is mediated by organic cation transporter 2 (OCT2), an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells. Metformin uptake into the liver, the site of action, is mediated by OCT1, which is expressed on the sinusoidal membrane of hepatocytes.

Effect of Cimetidine on Metformin Pharmacokinetics and Endogenous Metabolite Levels in Rats.

Tubular secretion is a primary mechanism along with glomerular filtration for renal elimination of drugs and toxicants into urine. Organic cation transporters (OCTs) and multidrug and toxic extrusion (MATE) transporters facilitate the active secretion of cationic substrates, including drugs such as metformin and endogenous cations. We hypothesized that administration of cimetidine, an Oct/Mate inhibitor, will result in increased plasma levels and decreased renal clearance of metformin and endogenous Oct/Mate substrates in rats.

Technical note: pig model for studying nutrient assimilation by the intestine and colon.

We have developed a system for chronically catheterizing 10- to 25-d-old pigs that permits stable isotope tracer studies of intestinal or colonic assimilation of nutrients. This model also can be used to ensure constant enteral feeding or to assess the rate of entry into the terminal ileum of carbohydrates, fats, and amino acids. A plastic cannula with a luminal flange can be surgically placed in the stomach for tracer studies of sugar digestion or for controlled infusion of any formula diet.

Measurement of the rate of entry of intact colon-derived lactose into the circulation: a model for assessing gut uptake of molecules not endogenously synthesized.

Background: Results of in vitro studies have documented colonic absorption of lactose in the newborn. A stable isotope model was developed for assessing the entry rate of intact lactose into the portal circulation in newborn piglets.

Methods: In experiment 1, unlabeled and [D-1-(13C)]-lactose were infused into two separate mesenteric veins, and in experiment 2, labeled lactose was infused into a mesenteric vein and unlabeled lactose was infused into the colon.

Stable isotope model for assessing production of short chain fatty acids from colon-derived sugar: application in pigs.

Sugar reaching the colon because of intestinal maldigestion or malabsorption may be fermented to acetate and other short-chain fatty acids, resulting in stimulation of colonic water absorption and cell proliferation. To explore this phenomenon in more detail, we have developed a stable isotope model for estimating the fraction of colon-derived glucose or lactose that is fermented to acetate, propionate and butyrate. In an initial application of the model, [d3]-acetate and either [1-(13)C]-glucose or [D-1-(13)C]-lactose were infused into the cecum or colon of piglets, and plateau plasma acetate enrichment was monitored in the carotid artery.