title: Modulation in concentrative nucleoside transporters-mediated intestinal absorption of mizoribine, an immunosuppressive agent, in lipopolysaccharide-treated rats.
abstract: The characteristics of intestinal absorption of mizoribine and cephalexin, that are mediated by concentrative nucleoside transporters (CNTs) and PEPT1, respectively, was examined in lipopolysaccharide (LPS)-treated rats. LPS treatment is known to modify the expression of some transporters and induce cholestasis. At 24 h after the LPS treatment, averaged concentrations of IL-6 and total bile acids in plasma were 15-fold and 2-fold that in untreated control rats, respectively, and bile flow rate decreased by 40% of control, indicating the induction of inflammatory and cholestatic states. The oral bioavailability, estimated by urinary excretion percentage of unchanged form, of mizoribine in LPS-treated rats was 1.5-fold higher than that in control rats, whereas the bioavailability of cephalexin remained unchanged. When mizoribine and cephalexin were administered into in-situ jejunum loops, there were no differences in the absorption rates between control and LPS-treated rats. These results indicated that the functional expression of CNT1, CNT2, and PEPT1 were not modulated by LPS treatment. When mizoribine (a CNT1/CNT2 substrate) and gemcitabin (a CNT1 substrate) were administered as a solution dissolved in bile into the intestinal loop, their absorption rates decreased significantly. In contrast, the absorption rate of ribavirin (a CNT2 substrate) remained unchanged. In conclusion, LPS treatment exerted no significant effect on the expression of CNT1 and CNT2 in the intestine. Bile was found to suppress the CNT1-mediated intestinal absorption of mizoribine and gemcitabin. The increased oral bioavailability of mizoribine in LPS-treated rats could be ascribed to the less amount of bile or bile acids in the intestine under cholestatic state of rats.
authors.affiliation: Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Mori
authors.forename: Y
authors.initials: Y
authors.lastname: Shimomukai
authors.forename: T
authors.initials: T
authors.lastname: Yokooji
authors.forename: M
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Y
authors.initials: Y
authors.lastname: Kamio
authors.forename: T
authors.initials: T
authors.lastname: Murakami
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000652:urine; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D002506:Cephalexin / Q000493:pharmacokinetics / Q000652:urine; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000652:urine; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D033703:Nucleoside Transport Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012254:Ribavirin / Q000493:pharmacokinetics; D012263:Ribonucleosides / Q000493:pharmacokinetics* / Q000652:urine; D000093542:Gemcitabine
chemical_list: D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D033703:Nucleoside Transport Proteins; D012263:Ribonucleosides; D003841:Deoxycytidine; D012254:Ribavirin; C010052:mizoribine; D002506:Cephalexin; D000093542:Gemcitabine