Characterization of intestinal absorption of mizoribine mediated by concentrative nucleoside transporters in rats.
Mizoribine, an imidazole nucleoside, is an inhibitor of purine synthesis and has been used as an orally available immunosuppressive agent in human renal transplantation. In the present study, the intestinal absorption of mizoribine was characterized by examining the contribution of concentrative nucleoside transporters (CNT1, CNT2) in rats. When mizoribine was administered orally in conscious rats, the bioavailability of mizoribine estimated by urinary excretion percentage of unchanged mizoribine was a dose dependent: 53.1+/-6.0% at 5 mg/kg and 24.0+/-5.1% at 20 mg/kg. In in-situ loop studies, the disappearance rate, or absorption rate, of mizoribine from the intestinal lumen was comparable between 1 and 5 mg/kg, but significantly lower at 25 mg/kg. Coadministration of adenosine (a substrate of both CNT1 and CNT2), thymidine (a CNT1 substrate) and inosine (a CNT2 substrate) significantly suppressed the intestinal mizoribine absorption, depending on the nucleoside concentrations coadministered. Gemcitabine (a pyrimidine nucleoside analogue, a CNT1 substrate) and ribavirin (a purine nucleoside analog, a CNT2 substrate) also significantly suppressed the mizoribine intestinal absorption. Bile salts such as sodium cholate and sodium glycocholate (10 mM) also significantly suppressed the intestinal mizoribine absorption, but not ribavirin absorption. Mizoribine is an amphoteric compound, however, the suppression of intestinal absorption by bile salts was not ascribed to the electrostatic interaction or micellar formation between mizoribine and bile salts. In conclusion, the intestinal absorption of mizoribine is mediated by CNT1 and CNT2, and nucleoside-derived drugs such as gemcitabine and ribavirin can suppress the intestinal absorption of mizoribine. Bile salts such as sodium glycocholate were also found to cause interaction with mizoribine.
Mori
Nobuhiro
N
Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Yokooji
Tomoharu
T
Kamio
Yoshihiro
Y
Murakami
Teruo
T
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000494:pharmacology; D001682:Biological Availability; D002352:Carrier Proteins / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D026901:Membrane Transport Proteins / Q000494:pharmacology*; D009705:Nucleosides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012254:Ribavirin / Q000494:pharmacology; D012263:Ribonucleosides / Q000493:pharmacokinetics*; D000093542:Gemcitabine
D000963:Antimetabolites; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D009705:Nucleosides; D012263:Ribonucleosides; C065171:cif nucleoside transporter; D003841:Deoxycytidine; D012254:Ribavirin; C010052:mizoribine; D000093542:Gemcitabine