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Characterization of Hepatobiliary Transport Systems of a Novel α4β1/α4β7 Dual Antagonist, TR-14035

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Abstract

Purpose

Our previous pharmacokinetic studies have demonstrated that TR-14035, a novel dual antagonist for α4β1/α4β7 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 μM, 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 μM, 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.

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Abbreviations

AUC:

area under the plasma concentration-time curve

BCRP:

breast cancer resistance protein

CL b :

biliary excretion clearance

CL r :

urinary excretion clearance

CL tot :

total body clearance

CYP:

cytochrome P450

EHBR:

Eisai hyperbilirubinemic rat

FCCP:

carbonyl cyanide-p-(trifluoromethoxy)-phenylhydrazone

K m :

Michaelis-Menten constant

k ns :

nonsaturable uptake clearance

KO:

knockout

LC-MSD:

liquid chromatography-mass spectrometric detection

LC-MS/MS:

liquid chromatography-tandem mass spectrometry

MDR:

multidrug resistance protein

MRP:

multidrug resistance-associated protein

MRT:

mean residence time

NTCP:

sodium/taurocholate cotransporting polypeptide

OAT:

organic anion transporter

OATP:

organic anion transporting polypeptide

OCT:

organic cation transporter

PAH:

p-aminohippuric acid

PPB:

plasma protein binding

SNP:

single nucleotide polymorphism

TEA:

tetraethylammonium

Vd :

volume of distribution

V max :

maximum uptake rate

References

  1. C. Berlin, E. L. Berg, M. J. Briskin, D. P. Andrew, P. J. Kilshaw, B. Holzmann, I. L. Weissman, A. Hamann, and E. C. Butcher. α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell74:185–195 (1993).

    Article  CAS  Google Scholar 

  2. C. Berlin, R. F. Bargatze, J. J. Campbell, U. H. von Andrian, M. C. Szabo, S. R. Hasslen, R. D. Nelson, E. L. Berg, S. L. Erlandsen, and E. C. Butcher. α4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell80:413–422 (1995).

    Article  CAS  Google Scholar 

  3. I. Sircar, K. S. Gudmundsson, R. Martin, J. Liang, S. Nomura, H. Jayakumar, B. R. Teegarden, D. M. Nowlin, P. M. Cardarelli, J. R. Mah, S. Connell, R. C. Griffith, and E. Lazarides. Synthesis and SAR of N-benzoyl-l-biphenylalanine derivatives: discovery of TR-14035, a dual α4β7/α4β1 integrin antagonist. Bioorg. Med. Chem.10:2051–2066 (2002).

    Article  CAS  Google Scholar 

  4. M. Tsuda-Tsukimoto, Y. Ogasawara, and T. Kume. Pharmacokinetics and metabolism of TR-14035, a novel antagonist of α4β1/α4β7 integrin mediated cell adhesion, in rat and dog. Xenobiotica35:373–389 (2005).

    Article  CAS  Google Scholar 

  5. M. Tsuda-Tsukimoto, Y. Ogasawara, and T. Kume. Role of human liver cytochrome P450 2C9 in the metabolism of a novel α4β1/α4β7 dual antagonist, TR-14035. Drug Metab. Pharmacokinet.20:127–134 (2005).

    Article  CAS  Google Scholar 

  6. B. Hagenbuch and P. J. Meier. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch.447:653–665 (2004).

    Article  CAS  Google Scholar 

  7. H. Koepsell and H. Endou. The SLC22 drug transporter family. Pflugers Arch.447:666–676 (2004).

    Article  CAS  Google Scholar 

  8. P. Chandra and K. L. Brouwer. The complexities of hepatic drug transport: current knowledge and emerging concepts. Pharm. Res.21:719–735 (2004).

    Article  CAS  Google Scholar 

  9. B. Sarkadi, C. Özvegy-Laczka, K. Német, and A. Váradi. ABCG2—a transporter for all seasons. FEBS Lett.567:116–120 (2004).

    Article  CAS  Google Scholar 

  10. H. Baur, S. Kasperek, and E. Pfaff. Criteria of viability of isolated liver cells. Hoppe-Seyler Z. Physiol. Chem.356:827–838 (1975).

    Article  CAS  Google Scholar 

  11. Y. Shitara, T. Itoh, H. Sato, A. P. Li, and Y. Sugiyama. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug–drug interaction between cerivastatin and cyclosporin A. J. Pharmacol. Exp. Ther.304:610–616 (2003).

    Article  CAS  Google Scholar 

  12. M. Schwenk. Transport systems of isolated hepatocytes: studies on the transport of biliary compounds. Arch.Toxicol.44:113–126 (1980).

    Article  CAS  Google Scholar 

  13. I. Tamai, T. Nozawa, M. Koshida, J. Nezu, Y. Sai, and A. Tsuji. Functional characterization of human organic anion transporting polypeptide B (OATP-B) in comparison with liver-specific OATP-C. Pharm. Res.18:1262–1269 (2001).

    Article  CAS  Google Scholar 

  14. M. Tsuda, T. Sekine, M. Takeda, S. H. Cha, Y. Kanai, M. Kimura, and H. Endou. Transport of ochratoxin A by renal multispecific organic anion transporter 1. J. Pharmacol. Exp. Ther.289:1301–1305 (1999).

    CAS  PubMed  Google Scholar 

  15. M. Jordan, A. Schallhorn, and F. M. Wurm. Transfecting mammalian cells: optimization of critical parameters affecting calcium–phosphate precipitate formation. Nucleic Acids Res.24:596–601 (1996).

    Article  CAS  Google Scholar 

  16. I. Tamai, J. Nezu, H. Uchino, Y. Sai, A. Oku, M. Shimane, and A. Tsuji. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun.273:251–260 (2000).

    Article  CAS  Google Scholar 

  17. K. Yamaoka, Y. Tanigawara, T. Nakagawa, and T. Uno. A pharmacokinetics analysis program (MULTI) for microcomputer. J. Pharmacobio-Dyn.4:879–885 (1981).

    Article  CAS  Google Scholar 

  18. W. Lee, H. Glaeser, L. H. Smith, R. L. Roberts, G. W. Moeckel, G. Gervasini, B. F. Leake, and R. B. Kim. Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J. Biol. Chem.280:9610–9617 (2005).

    Article  CAS  Google Scholar 

  19. M. Hirano, K. Maeda, H. Hayashi, H. Kusuhara, and Y. Sugiyama. Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J. Pharmacol. Exp. Ther.314:876–882 (2005).

    Article  CAS  Google Scholar 

  20. R. G. Tirona, B. F. Leake, G. Merino, and R. B. Kim. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J. Biol. Chem.276:35669–35675 (2001).

    Article  CAS  Google Scholar 

  21. T. Nozawa, M. Nakajima, I. Tamai, K. Noda, J. Nezu, Y. Sai, A. Tsuji, and T. Yokoi. Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J. Pharmacol. Exp. Ther.302:804–813 (2002).

    Article  CAS  Google Scholar 

  22. M. Iwai, H. Suzuki, I. Ieiri, K. Otsubo, and Y. Sugiyama. Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C). Pharmacogenetics14:749–757 (2004).

    Article  CAS  Google Scholar 

  23. T. Nozawa, S. Sugiura, M. Nakajima, A. Goto, T. Yokoi, J. Nezu, A. Tsuji, and I. Tamai. Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab. Dispos.32:291–294 (2004).

    Article  Google Scholar 

  24. T. Nozawa, H. Minami, S. Sugiura, A. Tsuji, and I. Tamai. 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. Drug Metab. Dispos.33:434–439 (2005).

    Article  CAS  Google Scholar 

  25. Y. Nishizato, I. Ieiri, H. Suzuki, M. Kimura, K. Kawabata, T. Hirota, H. Takane, S. Irie, H. Kusuhara, Y. Urasaki, A. Urae, S. Higuchi, K. Otsubo, and Y. Sugiyama. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther.73:554–565 (2003).

    Article  CAS  Google Scholar 

  26. M. Niemi, E. Schaeffeler, T. Lang, M. F. Fromm, M. Neuvonen, C. Kyrklund, J. T. Backman, R. Kerb, M. Schwab, P. J. Neuvonen, M. Eichelbaum, and K. T. Kivistö. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics14:429–440 (2004).

    Article  CAS  Google Scholar 

  27. M. Niemi, K. T. Kivistö, U. Hofmann, M. Schwab, M. Eichelbaum, and M. F. Fromm. Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). Br. J. Clin. Pharmacol.59:602–604 (2005).

    Article  CAS  Google Scholar 

  28. Y. Kameyama, K. Yamashita, K. Kobayashi, M. Hosokawa, and K. Chiba. 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. Pharmacogenet. Genomics15:513–522 (2005).

    Article  CAS  Google Scholar 

  29. M. Niemi, J. T. Backman, L. I. Kajosaari, J. B. Leathart, M. Neuvonen, A. K. Daly, M. Eichelbaum, K. T. Kivistö, and P. J. Neuvonen. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin. Pharmacol. Ther.77:468–478(2005).

    Article  CAS  Google Scholar 

  30. Y. Shitara, H. Sato, and Y. Sugiyama. Evaluation of drug–drug interaction in the hepatobiliary and renal transport of drugs. Annu. Rev. Pharmacol. Toxicol.45:689–723 (2005).

    Article  CAS  Google Scholar 

  31. S. G. Simonson, A. Raza, P. D. Martin, P. D. Mitchell, J. A. Jarcho, C. D. Brown, A. S. Windass, and D. W. Schneck. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin. Pharmacol. Ther.76:167–177 (2004).

    Article  CAS  Google Scholar 

  32. D. W. Schneck, B. K. Birmingham, J. A. Zalikowski, P. D. Mitchell, Y. Wang, P. D. Martin, K. C. Lasseter, C. D. Brown, A. S. Windass, and A. Raza. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin. Pharmacol. Ther.75:455–463 (2004).

    Article  CAS  Google Scholar 

  33. C.-Y. Wu and L. Z. Benet. Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine and GG918. Drug Metab. Dispos.31:1292–1295 (2003).

    Article  CAS  Google Scholar 

  34. Y. Y. Lau, C. -Y. Wu, H. Okochi, and L. Z. Benet. Ex situ inhibition of hepatic uptake and efflux significantly changes metabolism: hepatic enzyme-transporter interplay. J. Pharmacol. Exp. Ther.308:1040–1045 (2004).

    Article  CAS  Google Scholar 

  35. L. Liu and K. S. Pang. The roles of transporters and enzymes in hepatic drug processing. Drug Metab. Dispos.33:1–9 (2005).

    Article  Google Scholar 

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Acknowledgments

We thank Yoko Togo, Masao Yamanouchi, Kyoko Ozawa and Masakatsu Takahashi for their expert technical assistance in biliary excretion studies.

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Authors and Affiliations

  1. Exploratory DMPK, Exploratory Toxicology & DMPK Research Laboratories, Tanabe Seiyaku Co. Ltd., 2-2-50, Kawagishi, Toda, Saitama, 335-8505, Japan

    Minoru Tsuda-Tsukimoto & Toshiyuki Kume

  2. Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan

    Tomoji Maeda, Takashi Iwanaga & Ikumi Tamai

Authors
  1. Minoru Tsuda-Tsukimoto
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  2. Tomoji Maeda
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  3. Takashi Iwanaga
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  4. Toshiyuki Kume
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  5. Ikumi Tamai
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Correspondence to Minoru Tsuda-Tsukimoto.

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Tsuda-Tsukimoto, M., Maeda, T., Iwanaga, T. et al. Characterization of Hepatobiliary Transport Systems of a Novel α4β1/α4β7 Dual Antagonist, TR-14035. Pharm Res 23, 2646–2656 (2006). https://doi.org/10.1007/s11095-006-9102-6

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  • DOI: https://doi.org/10.1007/s11095-006-9102-6

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