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Intestinal Absorption of Alogliptin Is Mediated by a Fruit-Juice-Sensitive Transporter
- Source :
- Biologicalpharmaceutical bulletin. 44(5)
- Publication Year :
- 2021
-
Abstract
- Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60-71%), despite its low lipophilicity (logP=-1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.
- Subjects :
- 0301 basic medicine
Male
Pharmaceutical Science
Administration, Oral
Organic Anion Transporters
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
Intestinal absorption
03 medical and health sciences
chemistry.chemical_compound
Food-Drug Interactions
0302 clinical medicine
Piperidines
medicine
Animals
Humans
Carnitine
Uracil
Pharmacology
Organic cation transport proteins
biology
Peptide transporter 1
Transporter
General Medicine
Rats
Organic anion-transporting polypeptide
Fruit and Vegetable Juices
030104 developmental biology
HEK293 Cells
Biochemistry
chemistry
Diabetes Mellitus, Type 2
Intestinal Absorption
DIDS
030220 oncology & carcinogenesis
Malus
biology.protein
Terfenadine
Caco-2 Cells
Alogliptin
medicine.drug
Citrus paradisi
Citrus sinensis
Half-Life
Subjects
Details
- ISSN :
- 13475215
- Volume :
- 44
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Biologicalpharmaceutical bulletin
- Accession number :
- edsair.doi.dedup.....0785346f11684c0a1aff1f70f594f1c7