Peptide Transporter 1 Is Responsible for Intestinal Uptake of the Dipeptide Glycylsarcosine: Studies in Everted Jejunal Rings from Wild-type and Pept1 Null Mice

• Published in: Journal of pharmaceutical sciences Vol. 100; no. 2; pp. 767 - 774
• Main Authors: Ma, Katherine, Hu, Yongjun, Smith, David E.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.02.2011; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Dipeptides - metabolism; General pharmacology; Hydrogen-Ion Concentration; in vitro models; intestinal absorption; Jejunum - metabolism; Kinetics; Medical sciences; membrane transport/transporters; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Transporter 1; peptide transporters; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Sodium - metabolism; Symporters - genetics; Symporters - metabolism; Temperature; transgenics; pharmacokinetics; peptide transporters; intestinal absorption; membrane transport/transporters; in vitro models; transgenics; Pharmaceutical technology; Peptides; Rodentia; Gut; In vitro; Uptake; Vertebrata; Mammalia; Absorption; Mouse; Membrane transport; Animal; Dipeptides; Pharmacokinetics; Carrier protein
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.22277

The purpose of this study was to determine the relative importance of peptide transporter 1 (PEPT1) in the uptake of peptides/mimetics from mouse small intestine, using glycylsarcosine (GlySar). After isolating jejunal tissue from wild-type and Pept1 null mice, 2cm intestinal segments were everted and mounted on glass rods for tissue uptake studies. [14C]GlySar (4μM) was studied as a function of time, temperature, sodium and pH, concentration, and potential inhibitors. Compared with wild-type animals, Pept1 null mice exhibited a 78% reduction in GlySar uptake at pH 6.0 at 37°C. GlySar uptake showed pH dependence, with peak values between pH 6.0 and 6.5 in wild-type animals, whereas no such tendency was observed in Pept1 null mice. GlySar exhibited Michaelis–Menten uptake kinetics and a minor nonsaturable component in wild-type animals. In contrast, GlySar uptake occurred only by a nonsaturable process in Pept1 null mice. GlySar uptake was significantly inhibited by dipeptides, aminocephalosporins, angiotensin-converting enzyme inhibitors, and the antiviral prodrug valacyclovir; these inhibitors had little, if any, effect on the uptake of GlySar in Pept1 null mice. The findings demonstrate that PEPT1 plays a critical role in the uptake of GlySar in jejunum and suggest that PEPT1 is the major transporter responsible for the intestinal absorption of small peptides.