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Vol. 289, Issue 1, 448-454, April 1999
Department of Pharmaceutics, College of Pharmacy, Rutgers
University, Piscataway, New Jersey
The results of previous work performed in our laboratory using
an in situ perfusion technique in rats and rabbit apical brush border
membrane vesicles have suggested that the intestinal uptake of
valacyclovir (VACV) appears to be mediated by multiple membrane transporters. Using these techniques, it is difficult to characterize the transport kinetics of VACV with each individual transporter in the
presence of multiple known or unknown transporters. The purpose of this
study was to characterize the interaction of VACV and the human
intestinal peptide transporter using Chinese hamster ovary (CHO) cells
that overexpress the human intestinal peptide transporter (hPEPT1)
gene. VACV uptake was significantly greater in CHO cells transfected
with hPEPT1 than in cells transfected with only the vector, pcDNA3. The
optimum pH for VACV uptake was determined to occur at pH 7.5. Proton
cotransport was not observed in hPEPT1/CHO cells, consistent with
previously observed results in tissues and Caco-2 cells. VACV uptake
was concentration dependent and saturable with a Michaelis-Menten
constant and maximum velocity of 1.64 ± 0.06 mM and 23.34 ± 0.36 nmol/mg protein/5 min, respectively. A very similar
Km value was obtained in hPEPT1/CHO cells
and in rat and rabbit tissues and Caco-2 cells, suggesting that hPEPT1 dominates the intestinal transport properties of VACV in vitro. VACV
uptake was markedly inhibited by various dipeptides and 
-lactam antibiotics, and Ki values of 12.8 ± 2.7 and 9.1 ± 1.2 mM were obtained for Gly-Sar and cefadroxil at
pH 7.5, respectively. The present results demonstrate that VACV is a
substrate for the human intestinal peptide transporter in hPEPT1/CHO
cells and that although transport is pH dependent, proton cotransport
is not apparent. Also, the results demonstrate that the hPEPT1/CHO cell
system has use in investigating the transport kinetics of drugs with the human intestinal peptide transporter hPEPT1; however, the extrapolation of these transport properties to the in vivo situation requires further investigation.
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