PEPT1 is a high-capacity, low-affinity peptide transporter that mediates the uptake of di-and tripeptides in the intestine and kidney. PEPT1 also has significance in its ability to transport therapeutic agents and because of its potential as a target for anti-inflammatory therapies. To further understand the relevance of specific peptide transporters in intestinal physiology, pharmacology and pathophysiology, we have generated Pept1 null mice by targeted gene disruption. The Pept1 gene was disrupted by insertion of a lacZ reporter gene under the control of the endogenous Pept1 promoter. Phenotypic profiling of wild-type and Pept1 null mice was then performed, along with in vitro intestinal uptake, in situ intestinal perfusion and in vivo pharmacokinetic studies of glycylsarcosine (GlySar). Pept1 null mice lacked expression of PEPT1 protein in the intestine and kidney, tissues in which this peptide transporter is normally expressed. Pept1-deficient mice were found to be viable, fertile, grew to normal size and weight, and were without any obvious abnormalities. Nevertheless, Pept1 deletion dramatically reduced the intestinal uptake and effective permeability of the model dipeptide GlySar (i.e., by at least 80%), and its oral absorption following gastric gavage (i.e., by about 50%). In contrast, the plasma profiles of GlySar were almost superimposable between wild-type and Pept1 null animals after intravenous dosing. These novel findings provide strong evidence that PEPT1 has a major role in the in vivo oral absorption of dipeptides.
ABSTRACT:The purpose of this study was to evaluate the role, relevance, and regional dependence of peptide transporter (PEPT) 1 expression and function in mouse intestines using the model dipeptide glycylsarcosine (GlySar). After isolating specific intestinal segments, in situ single-pass perfusions were performed in wild-type and Pept1 knockout mice.
Background. A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug-drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs).Methods. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs.Results. A search of the AERS database and existing literature found several individual case reports of drug-drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.