Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Pharm Res
2006 Nov 01;2311:2646-56. doi: 10.1007/s11095-006-9102-6.
Show Gene links
Show Anatomy links
Characterization of hepatobiliary transport systems of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035.
Tsuda-Tsukimoto M
,
Maeda T
,
Iwanaga T
,
Kume T
,
Tamai I
.
???displayArticle.abstract???
PURPOSE: Our previous pharmacokinetic studies have demonstrated that TR-14035, a novel dual antagonist for alpha4beta1/alpha4beta7 integrin, selectively and strongly accumulated in the liver and was mainly excreted in bile as an unchanged drug. In the present study, we investigated the hepatobiliary transport system in detail.
MATERIALS AND METHODS: Uptake by hepatocytes and organic anion transporting polypeptide (OATP)-expressing Xenopus laevis oocytes or Flp-In-293 cells was performed in vitro. Biliary excretion was investigated in mdr1a/b-knockout mice, Bcrp-knockout mice and Mrp2-defective Eisai hyperbilirubinemic rats (EHBRs).
RESULTS: TR-14035 was taken up by rat and human hepatocytes by an apparently single saturable mechanism with K(m) of 6.7 and 2.1 microM, respectively, and taurocholate and digoxin reduced this uptake. OATP1B1/OATP-C and OATP1B3/OATP8 expressed in oocytes mediated the TR-14035 uptake with K(m) of 7.5 and 5.3 microM, respectively. OATP1B1*15, a genetic variant of OATP1B1, exhibited a decreased transport of TR-14035 compared with OATP1B1*1a. Biliary excretion and total body clearance of unchanged TR-14035 in EHBRs were significantly lower than those in normal rats, while there was no difference in the clearances between wild and mdr1a/b- or Bcrp-knockout mice.
CONCLUSION: These results indicate that OATP1B1 and OATP1B3 are at least partly responsible for the accumulation of TR-14035 into hepatocytes, and Mrp2 principally mediates the biliary excretion of TR-14035. Furthermore, genetic polymorphisms of OATP1B1 may cause an interindividual variability in the pharmacokinetics of TR-14035.
Baur,
Criteria of viability of isolated liver cells.
1975, Pubmed
Baur,
Criteria of viability of isolated liver cells.
1975,
Pubmed
Berlin,
alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow.
1995,
Pubmed
Berlin,
Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1.
1993,
Pubmed
Chandra,
The complexities of hepatic drug transport: current knowledge and emerging concepts.
2004,
Pubmed
Hagenbuch,
Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties.
2004,
Pubmed
Hirano,
Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin.
2005,
Pubmed
Iwai,
Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C).
2004,
Pubmed
Jordan,
Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation.
1996,
Pubmed
Kameyama,
Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells.
2005,
Pubmed
Koepsell,
The SLC22 drug transporter family.
2004,
Pubmed
Lau,
Ex situ inhibition of hepatic uptake and efflux significantly changes metabolism: hepatic enzyme-transporter interplay.
2004,
Pubmed
Lee,
Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry.
2005,
Pubmed
Liu,
The roles of transporters and enzymes in hepatic drug processing.
2005,
Pubmed
Niemi,
High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1).
2004,
Pubmed
Niemi,
Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1).
2005,
Pubmed
Niemi,
Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics.
2005,
Pubmed
Nishizato,
Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics.
2003,
Pubmed
Nozawa,
Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity.
2004,
Pubmed
,
Xenbase
Nozawa,
Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis.
2002,
Pubmed
Nozawa,
Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms.
2005,
Pubmed
,
Xenbase
Sarkadi,
ABCG2 -- a transporter for all seasons.
2004,
Pubmed
Schneck,
The effect of gemfibrozil on the pharmacokinetics of rosuvastatin.
2004,
Pubmed
,
Xenbase
Schwenk,
Transport systems of isolated hepatocytes. Studies on the transport of biliary compounds.
1980,
Pubmed
Shitara,
Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs.
2005,
Pubmed
Shitara,
Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A.
2003,
Pubmed
Simonson,
Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine.
2004,
Pubmed
,
Xenbase
Sircar,
Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist.
2002,
Pubmed
Tamai,
Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family.
2000,
Pubmed
Tamai,
Functional characterization of human organic anion transporting polypeptide B (OATP-B) in comparison with liver-specific OATP-C.
2001,
Pubmed
,
Xenbase
Tirona,
Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans.
2001,
Pubmed
Tsuda,
Transport of ochratoxin A by renal multispecific organic anion transporter 1.
1999,
Pubmed
,
Xenbase
Tsuda-Tsukimoto,
Role of human liver cytochrome P450 2C9 in the metabolism of a novel alpha4beta1/alpha4beta7 dual antagonist, TR-14035.
2005,
Pubmed
Tsuda-Tsukimoto,
Pharmacokinetics and metabolism of TR-14035, a novel antagonist of a4ss1/a4ss7 integrin mediated cell adhesion, in rat and dog.
2005,
Pubmed
Wu,
Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine, and gg918.
2003,
Pubmed
Yamaoka,
A pharmacokinetic analysis program (multi) for microcomputer.
1981,
Pubmed
