Pharmaceutical Research

, Volume 22, Issue 8, pp 1406–1410 | Cite as

Inhibitory Effects of Various Beverages on Ritodrine Sulfation by Recombinant Human Sulfotransferase Isoforms SULT1A1 and SULT1A3

  • Haruka Nishimuta
  • Masayuki Tsujimoto
  • Kenichiro Ogura
  • Akira Hiratsuka
  • Hisakazu Ohtani
  • Yasufumi Sawada
Short Communication


Ritodrine is known to undergo extensive presystemic sulfation in the intestinal mucosa, and its bioavailability is as low as 30%. Accordingly, inhibition of intestinal sulfation may lead to an increase in the bioavailability of ritodrine. In this study, we aimed to investigate the activities of ritodrine sulfation by SULT1A1, which is expressed predominantly in the liver, and SULT1A3, which is expressed predominantly in the intestine, as well as the inhibitory effects of beverages on their activities.


We investigated ritodrine sulfation by using recombinant human sulfotransferase (SULT) 1A1 and SULT1A3 in an in vitro study. Next, we investigated the inhibitory effects of grapefruit juice, orange juice, green tea, and black tea on ritodrine sulfation.


Sulfation of ritodrine by SULT1A3 was much higher than that by SULT1A1, suggesting that the bioavailability of ritodrine may be limited by intestinal SULT1A3. The ritodrine sulfation activities of SULT1A1 and SULT1A3 were significantly inhibited by all beverages examined at a concentration of 10%. Green tea and black tea exhibited potent inhibition; even at a concentration of 5%, they both inhibited SULT1A1 by 100% and SULT1A3 by ≥95%.


Our results suggest that concomitant ingestion of beverages such as green tea and black tea may increase the bioavailability of orally administered ritodrine, and perhaps other β2-agonists, and lead to an increase in the clinical effects or adverse reactions.

Key Words

drug-food interaction enzyme inhibitors intestinal bioavailability ritodrine sulfotransferase 



3′-phosphoadenosine 5′-phosphosulfate




  1. 1.
    Hosenpud, J. D., Morton, M. J., O’Grady, J. P. 1983Cardiac stimulation during ritodrine hydrochloride tocolytic therapyObstet. Gynecol.625258PubMedGoogle Scholar
  2. 2.
    Brashear, W. T., Kuhnert, B. R., Wei, R. 1990Structural determination of the conjugated metabolites of ritodrineDrug Metab. Dispos.18488493PubMedGoogle Scholar
  3. 3.
    Brashear, W. T., Kuhnert, B. R., Wei, R. 1988Maternal and neonatal urinary excretion of sulfate and glucuronide ritodrine conjugatesClin. Pharmacol. Ther.44634641PubMedGoogle Scholar
  4. 4.
    Pacifici, G. M., Quilici, M. C., Giulianetti, B., Spisni, R., Nervi, M., Giuliani, L., Gomeni, R. 1998Ritodrine sulphation in the human liver and duodenal mucosa: interindividual variabilityEur. J. Drug Metab. Pharmacokinet.236774PubMedGoogle Scholar
  5. 5.
    Cappiello, M., Giuliani, L., Pacifici, G. M. 1990Differential distribution of phenol and catechol sulphotransferases in human liver and intestinal mucosaPharmacology406976PubMedGoogle Scholar
  6. 6.
    Bronner, W. E., Beecher, G. R. 1998Method for determining the content of catechins in tea infusions by high-performance liquid chromatographyJ. Chromatogr. A805137142CrossRefPubMedGoogle Scholar
  7. 7.
    Coughtrie, M. W., Johnston, L. E. 2001Interactions between dietary chemicals and human sulfotransferases—molecular mechanisms and clinical significanceDrug Metab. Dispos.29522528PubMedGoogle Scholar
  8. 8.
    Nishiyama, T., Ogura, K., Nakano, H., Kaku, T., Takahashi, E., Ohkubo, Y., Sekine, K., Hiratsuka, A., Kadota, S., Watabe, T. 2002Sulfation of environmental estrogens by cytosolic human sulfotransferasesDrug Metab. Pharmacokinet.17221228CrossRefPubMedGoogle Scholar
  9. 9.
    Nakano, H., Ogura, K., Takahashi, E., Harada, T., Nishiyama, T., Muro, K., Hiratsuka, A., Kadota, S., Watabe, T. 2004Regioselective monosulfation and disulfation of the phytoestrogens daidzein and genistein by human liver sulfotransferasesDrug Metab. Pharmacokinet.19216226CrossRefPubMedGoogle Scholar
  10. 10.
    Sekura, R. D., Marcus, C. J., Lyon, E. S., Jakoby, W. B. 1979Assay of sulfotransferasesAnal. Biochem.958286CrossRefPubMedGoogle Scholar
  11. 11.
    Sundaram, R. S., Szumlanski, C., Otterness, D., Loon, J. A., Weinshilboum, R. M. 1989Human intestinal phenol sulfotransferase: assay conditions, activity levels and partial purification of the thermolabile formDrug Metab. Dispos.17255264PubMedGoogle Scholar
  12. 12.
    Ma, B., Shou, M., Schrag, M. L. 2003Solvent effect on cDNA-expressed human sulfotransferase (SULT) activities in vitroDrug Metab. Dispos.3113001305CrossRefPubMedGoogle Scholar
  13. 13.
    Chen, G., Zhang, D., Jing, N., Yin, S., Falany, C. N., Radominska-Pandya, A. 2003Human gastrointestinal sulfotransferases: identification and distributionToxicol. Appl. Pharmacol.187186197CrossRefPubMedGoogle Scholar
  14. 14.
    Wang, J., Falany, J. L., Falany, C. N. 1998Expression and characterization of a novel thyroid hormone-sulfating form of cytosolic sulfotransferase from human liverMol. Pharmacol.53274282PubMedGoogle Scholar
  15. 15.
    Hochhaus, G., Mollmann, H. 1992Pharmacokinetic/pharmacodynamic characteristics of the beta-2-agonists terbutaline, salbutamol and fenoterolInt. J. Clin. Pharmacol. Ther. Toxicol.30342362PubMedGoogle Scholar
  16. 16.
    Shen, D. D., Kunze, K. L., Thummel, K. E. 1997Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extractionAdv. Drug Deliv. Rev.2799127CrossRefPubMedGoogle Scholar
  17. 17.
    Hildebrandt, R., Wagner, B., Preiss-Nowzohour, K., Gundert-Remy, U. 1994Fenoterol metabolism in man: sulphation versus glucuronidationXenobiotica247177PubMedGoogle Scholar
  18. 18.
    Tegner, K., Nilsson, H. T., Persson, C. G., Persson, K., Ryrfeldt, A. 1984Elimination pathways of terbutalineEur. J. Respir. Dis., Suppl.13493100Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Haruka Nishimuta
    • 1
  • Masayuki Tsujimoto
    • 1
  • Kenichiro Ogura
    • 2
  • Akira Hiratsuka
    • 2
  • Hisakazu Ohtani
    • 1
  • Yasufumi Sawada
    • 1
  1. 1.Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Drug Metabolism and Molecular Toxicology, School of PharmacyTokyo University of Pharmacy and Life ScienceTokyoJapan

Personalised recommendations