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.
Footnotes
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This work was supported by the 21st Century Center of Excellence Program “Knowledge Information Infrastructure for Genome Science,” the Leading Project for Biosimulation, a grant-in-aid for Scientific Research from the Ministry of Education, Culture and Sports of Japan, and a grant-in-aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.102830.
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ABBREVIATIONS: PEPT1, H+-coupled peptide transporter 1; DMAE, 1-(2′,5′-dimethoxyphenyl)-2-aminoethanol; MES, 2-(N-morpholino)ethanesulfonic acid; HPLC, high-performance liquid chromatography; TFA, trifluoroacetic acid; AUC, area under the curve.
- Received February 12, 2006.
- Accepted April 4, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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