Submitted on June 23, 2004
Accepted on November 3, 2004
Increased protein level of PEPT1 intestinal H+/peptide cotransporter up-regulates absorption of glycylsarcosine and ceftibuten in 5/6 nephrectomized rats
Yuriko Shimizu1, Satohiro Masuda1, Kumiko Nishihara1, Lin Ji1, Masahiro Okuda1, and Ken-ichi Inui1*
1 Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto, Japan
* To whom correspondence should be addressed. E-mail: inui{at}kuhp.kyoto-u.ac.jp.
In chronic renal failure (CRF), dietary protein is one of the factors to
deteriorate residual renal functions. Numerous studies have indicated that
the products of protein digestion are mainly absorbed as small peptides.
However, how small peptides are absorbed in CRF remains poorly
understood. H+-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 [14C]glycylsarcosine and ceftibuten
was significantly increased in 5/6 NR rats in comparison with sham-operated
rats, without changing the 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 indicated that the increase in
absorption of small peptides and peptide-like drugs, caused by the up-regulation
of intestinal PEPT1 protein, might contribute to the progression
of renal failure as well as the alteration of drug pharmacokinetics.
