Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepT1.
In the present study, possible enhancement of intestinal absorption of L-dopa by utilizing intestinal peptide transporter was examined using Caco-2 cells and Xenopus oocytes expressing human peptide transporter (hPepT1). To see whether this peptide transporter could be utilized for the improvement of L-dopa absorption, we employed a dipeptide-mimetic derivative of L-dopa, L-dopa-L-Phe. L-Dopa-L-Phe inhibited the uptake of [14C]Gly-Sar, but not that of L-[3H]-dopa by Caco-2 cells. Uptake of L-dopa-L-Phe was increased by expression of hPepT1 in Xenopus oocytes. The appearance of L-dopa and its metabolite, dopamine, on the basolateral side of Caco-2 cells was significantly higher after addition of L-dopa-L-Phe than after that of L-dopa and was reduced by the presence of Gly-Sar on the apical side. These results indicate that the L-dopa-L-Phe is absorbed more efficiently than L-dopa and is taken up via the peptide transporter, but not via the amino acid transporter, demonstrating the possibility of targeting the peptide transporter as a means for improving intestinal absorption of peptide-like drugs.
Tamai
I
I
Department of Pharmacobio-dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Nakanishi
T
T
Nakahara
H
H
Sai
Y
Y
Ganapathy
V
V
Leibach
F H
FH
Tsuji
A
A
D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000493:pharmacokinetics; D000818:Animals; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D015820:Cadherins; D002352:Carrier Proteins / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005768:Gastrointestinal Hormones / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption; D007980:Levodopa / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D026901:Membrane Transport Proteins; D009865:Oocytes / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014981:Xenopus
D026905:Amino Acid Transport Systems; D000596:Amino Acids; C490584:CDH17 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D005768:Gastrointestinal Hormones; D026901:Membrane Transport Proteins; C067802:intestinal peptide-proton cotransporter; D007980:Levodopa