Document Detail

Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives.
MedLine Citation:
PMID:  16597710     Owner:  NLM     Status:  MEDLINE    
Midodrine is an oral drug for orthostatic hypotension. This drug is almost completely absorbed after oral administration and converted into its active form, 1-(2',5'-dimethoxyphenyl)-2-aminoethanol) (DMAE), by the cleavage of a glycine residue. The intestinal H+-coupled peptide transporter 1 (PEPT1) transports various peptide-like drugs and has been used as a target molecule for improving the intestinal absorption of poorly absorbed drugs through amino acid modifications. Because midodrine meets these requirements, we examined whether midodrine can be a substrate for PEPT1. The uptake of midodrine, but not DMAE, was markedly increased in PEPT1-expressing oocytes compared with water-injected oocytes. Midodrine uptake by Caco-2 cells was saturable and was inhibited by various PEPT1 substrates. Midodrine absorption from the rat intestine was very rapid and was significantly inhibited by the high-affinity PEPT1 substrate cyclacillin, assessed by the alteration of the area under the blood concentration-time curve for 30 min and the maximal concentration. Some amino acid derivatives of DMAE were transported by PEPT1, and their transport was dependent on the amino acids modified. In contrast to neutral substrates, cationic midodrine was taken up extensively at alkaline pH, and this pH profile was reproduced by a 14-state model of PEPT1, which we recently reported. These findings indicate that PEPT1 can transport midodrine and contributes to the high bioavailability of this drug and that Gly modification of DMAE is desirable for a prodrug of DMAE.
Masahiro Tsuda; Tomohiro Terada; Megumi Irie; Toshiya Katsura; Ayumu Niida; Kenji Tomita; Nobutaka Fujii; Ken-ichi Inui
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-04-05
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  318     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-06-22     Completed Date:  2006-08-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  455-60     Citation Subset:  IM    
Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.
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MeSH Terms
Amino Acids / chemistry,  metabolism*,  therapeutic use
Caco-2 Cells
Dose-Response Relationship, Drug
Hypotension, Orthostatic / drug therapy,  metabolism*
Membrane Transport Proteins / chemistry,  metabolism*,  therapeutic use
Midodrine / chemistry,  metabolism*,  therapeutic use
Protein Transport / drug effects,  physiology
Xenopus laevis
Reg. No./Substance:
0/Amino Acids; 0/Membrane Transport Proteins; 42794-76-3/Midodrine; 97599-47-8/peptide permease

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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