title: Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives.
abstract: 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.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terada
authors.forename: Megumi
authors.initials: M
authors.lastname: Irie
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Ayumu
authors.initials: A
authors.lastname: Niida
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomita
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007024:Hypotension, Orthostatic / Q000188:drug therapy / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D008879:Midodrine / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D009865:Oocytes; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D014982:Xenopus laevis
chemical_list: D000596:Amino Acids; D026901:Membrane Transport Proteins; D008879:Midodrine; C043912:peptide permease