Involvement of organic anion transporting polypeptide 1a5 (Oatp1a5) in the intestinal absorption of endothelin receptor antagonist in rats.
OBJECTIVE
To assess the contribution of organic anion transporting polypeptide 1a5 (Oatp1a5/Oatp3) in the intestinal absorption of an orally active endothelin receptor antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylene-dioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (compound-A) in rats.


METHODS
Uptakes of [(14)C]compound-A by Oatp1a5-expressing Xenopus laevis oocytes and isolated rat enterocytes were evaluated.


RESULTS
The uptake of compound-A by Oatp1a5-expressing oocytes was significantly higher than that by water-injected oocytes and Oatp1a5-mediated uptake was saturable with K(m) value of 116 microM. Compound-A was taken up into isolated enterocytes in time- and concentration-dependent manners and the estimated K(m) value was 83 microM, which was close to that for the Oatpt1a5-mediated uptake in oocytes. Both uptakes of compound-A by Oatp1a5-expressing oocytes and enterocytes were pH-sensitive with significantly higher uptake at acidic pH than those at neutral pH. Uptakes of compound-A into Oatp1a5-expressing oocytes and enterocytes were significantly decreased in the presence of Oatp1a5 substrates such as bromosulfophthalein and taurocholic acid.


CONCLUSIONS
These results consistently suggested that Oatp1a5 is contributing to the intestinal absorption of compound-A at least in part, and the transporter-mediated absorption seems to be maximized at the acidic microenvironment of epithelial cells in the small intestine in rats.
Tani
Takeshi
T
Drug Metabolism, Tsukuba Research Institute, Banyu Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan.
Gram
Luise K
LK
Arakawa
Hiroshi
H
Kikuchi
Akihiro
A
Chiba
Masato
M
Ishii
Yasuyuki
Y
Steffansen
Bente
B
Tamai
Ikumi
I
D000818:Animals; D003627:Data Interpretation, Statistical; D065128:Endothelin Receptor Antagonists; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects* / Q000235:genetics*; D007700:Kinetics; D008297:Male; D009865:Oocytes / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D013448:Sulfobromophthalein; D014982:Xenopus laevis
D065128:Endothelin Receptor Antagonists; D029362:Organic Anion Transporters, Sodium-Independent; D011725:Pyridines; C421143:Slco1a5 protein, rat; D013448:Sulfobromophthalein; C119319:J 104132