Orange Juice and Its Component, Hesperidin, Decrease the Expression of Multidrug Resistance-Associated Protein 2 in Rat Small Intestine and Liver
Identifieur interne : 000E23 ( Pmc/Checkpoint ); précédent : 000E22; suivant : 000E24Orange Juice and Its Component, Hesperidin, Decrease the Expression of Multidrug Resistance-Associated Protein 2 in Rat Small Intestine and Liver
Auteurs : Minoru Watanabe ; Naoki Matsumoto [Japon] ; Yuko Takeba [Japon] ; Toshio Kumai ; Masami Tanaka ; Shinobu Tatsunami [Japon] ; Sachiko Takenoshita-Nakaya [Japon] ; Yoshie Harimoto [Japon] ; Yuichi Kinoshita [Japon] ; Shinichi Kobayashi [Japon]Source :
- Journal of Biomedicine and Biotechnology [ 1110-7243 ] ; 2011.
Abstract
We investigated the effects of orange juice (OJ) or hesperidin, a component of OJ, on the pharmacokinetics of pravastatin (PRV) and the expression of both protein and mRNA of multidrug resistance-associated protein 2 (Mrp2) in the rat small intestine and liver. Eight-week-old male Sprague-Dawley rats were used in this study. OJ or a 0.079% hesperidin suspension was administered orally for 2 days. Tap water was given as a control. A single dose of PRV at 100 mg/kg p.o. was administered after 2 days of OJ, hesperidin, or tap water ingestion. The AUC,
Url:
DOI: 10.1155/2011/502057
PubMed: 21660137
PubMed Central: 3110312
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Orange Juice and Its Component, Hesperidin, Decrease the Expression of Multidrug Resistance-Associated Protein 2 in Rat Small Intestine and Liver</title><author><name sortKey="Watanabe, Minoru" sort="Watanabe, Minoru" uniqKey="Watanabe M" first="Minoru" last="Watanabe">Minoru Watanabe</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Matsumoto, Naoki" sort="Matsumoto, Naoki" uniqKey="Matsumoto N" first="Naoki" last="Matsumoto">Naoki Matsumoto</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Takeba, Yuko" sort="Takeba, Yuko" uniqKey="Takeba Y" first="Yuko" last="Takeba">Yuko Takeba</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Kumai, Toshio" sort="Kumai, Toshio" uniqKey="Kumai T" first="Toshio" last="Kumai">Toshio Kumai</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Tanaka, Masami" sort="Tanaka, Masami" uniqKey="Tanaka M" first="Masami" last="Tanaka">Masami Tanaka</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Tatsunami, Shinobu" sort="Tatsunami, Shinobu" uniqKey="Tatsunami S" first="Shinobu" last="Tatsunami">Shinobu Tatsunami</name><affiliation wicri:level="1"><nlm:aff id="I4">Unit of Medical Statistics, Faculty of Medical Education and Culture, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Unit of Medical Statistics, Faculty of Medical Education and Culture, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Takenoshita Nakaya, Sachiko" sort="Takenoshita Nakaya, Sachiko" uniqKey="Takenoshita Nakaya S" first="Sachiko" last="Takenoshita-Nakaya">Sachiko Takenoshita-Nakaya</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Harimoto, Yoshie" sort="Harimoto, Yoshie" uniqKey="Harimoto Y" first="Yoshie" last="Harimoto">Yoshie Harimoto</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Kinoshita, Yuichi" sort="Kinoshita, Yuichi" uniqKey="Kinoshita Y" first="Yuichi" last="Kinoshita">Yuichi Kinoshita</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Kobayashi, Shinichi" sort="Kobayashi, Shinichi" uniqKey="Kobayashi S" first="Shinichi" last="Kobayashi">Shinichi Kobayashi</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21660137</idno><idno type="pmc">3110312</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110312</idno><idno type="RBID">PMC:3110312</idno><idno type="doi">10.1155/2011/502057</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">001007</idno><idno type="wicri:Area/Pmc/Curation">001006</idno><idno type="wicri:Area/Pmc/Checkpoint">000E23</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Orange Juice and Its Component, Hesperidin, Decrease the Expression of Multidrug Resistance-Associated Protein 2 in Rat Small Intestine and Liver</title><author><name sortKey="Watanabe, Minoru" sort="Watanabe, Minoru" uniqKey="Watanabe M" first="Minoru" last="Watanabe">Minoru Watanabe</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Matsumoto, Naoki" sort="Matsumoto, Naoki" uniqKey="Matsumoto N" first="Naoki" last="Matsumoto">Naoki Matsumoto</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Takeba, Yuko" sort="Takeba, Yuko" uniqKey="Takeba Y" first="Yuko" last="Takeba">Yuko Takeba</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Kumai, Toshio" sort="Kumai, Toshio" uniqKey="Kumai T" first="Toshio" last="Kumai">Toshio Kumai</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Tanaka, Masami" sort="Tanaka, Masami" uniqKey="Tanaka M" first="Masami" last="Tanaka">Masami Tanaka</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Tatsunami, Shinobu" sort="Tatsunami, Shinobu" uniqKey="Tatsunami S" first="Shinobu" last="Tatsunami">Shinobu Tatsunami</name><affiliation wicri:level="1"><nlm:aff id="I4">Unit of Medical Statistics, Faculty of Medical Education and Culture, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Unit of Medical Statistics, Faculty of Medical Education and Culture, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Takenoshita Nakaya, Sachiko" sort="Takenoshita Nakaya, Sachiko" uniqKey="Takenoshita Nakaya S" first="Sachiko" last="Takenoshita-Nakaya">Sachiko Takenoshita-Nakaya</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Harimoto, Yoshie" sort="Harimoto, Yoshie" uniqKey="Harimoto Y" first="Yoshie" last="Harimoto">Yoshie Harimoto</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Kinoshita, Yuichi" sort="Kinoshita, Yuichi" uniqKey="Kinoshita Y" first="Yuichi" last="Kinoshita">Yuichi Kinoshita</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author><author><name sortKey="Kobayashi, Shinichi" sort="Kobayashi, Shinichi" uniqKey="Kobayashi S" first="Shinichi" last="Kobayashi">Shinichi Kobayashi</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511</wicri:regionArea><wicri:noRegion>Kanagawa 216-8511</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of Biomedicine and Biotechnology</title><idno type="ISSN">1110-7243</idno><idno type="eISSN">1110-7251</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We investigated the effects of orange juice (OJ) or hesperidin, a component of OJ, on the pharmacokinetics of pravastatin (PRV) and the expression of both protein and mRNA of multidrug resistance-associated protein 2 (Mrp2) in the rat small intestine and liver. Eight-week-old male Sprague-Dawley rats were used in this study. OJ or a 0.079% hesperidin suspension was administered orally for 2 days. Tap water was given as a control. A single dose of PRV at 100 mg/kg p.o. was administered after 2 days of OJ, hesperidin, or tap water ingestion. The AUC, <italic>C</italic><sub>max</sub>, and <italic>t</italic><sub>1/2</sub> values of PRV were significantly increased in OJ group. Mrp2 protein and mRNA levels in the small intestine and liver, respectively, were significantly decreased after the ingestion of OJ. The same results were obtained with hesperidin. These results suggest that the changes in PRV pharmacokinetic parameters and the decrease in Mrp2 expression caused by OJ are due to hesperidin in the juice.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Tian, R" uniqKey="Tian R">R Tian</name></author><author><name sortKey="Koyabu, N" uniqKey="Koyabu N">N Koyabu</name></author><author><name sortKey="Takanaga, H" uniqKey="Takanaga H">H Takanaga</name></author><author><name sortKey="Matsuo, H" uniqKey="Matsuo H">H Matsuo</name></author><author><name sortKey="Ohtani, H" uniqKey="Ohtani H">H Ohtani</name></author><author><name sortKey="Sawada, Y" uniqKey="Sawada Y">Y Sawada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dresser, Gk" uniqKey="Dresser G">GK Dresser</name></author><author><name sortKey="Bailey, Dg" uniqKey="Bailey D">DG Bailey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haria, M" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Biomed Biotechnol</journal-id><journal-id journal-id-type="publisher-id">JBB</journal-id><journal-title-group><journal-title>Journal of Biomedicine and Biotechnology</journal-title></journal-title-group><issn pub-type="ppub">1110-7243</issn><issn pub-type="epub">1110-7251</issn><publisher><publisher-name>Hindawi Publishing Corporation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21660137</article-id><article-id pub-id-type="pmc">3110312</article-id><article-id pub-id-type="doi">10.1155/2011/502057</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Orange Juice and Its Component, Hesperidin, Decrease the Expression of Multidrug Resistance-Associated Protein 2 in Rat Small Intestine and Liver</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Watanabe</surname><given-names>Minoru</given-names></name><xref ref-type="aff" rid="I1"><sup>1, 2</sup></xref><xref ref-type="aff" rid="I2"></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Matsumoto</surname><given-names>Naoki</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Takeba</surname><given-names>Yuko</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kumai</surname><given-names>Toshio</given-names></name><xref ref-type="aff" rid="I1"><sup>1, 3</sup></xref><xref ref-type="aff" rid="I3"></xref></contrib><contrib contrib-type="author"><name><surname>Tanaka</surname><given-names>Masami</given-names></name><xref ref-type="aff" rid="I1"><sup>1, 2</sup></xref><xref ref-type="aff" rid="I2"></xref></contrib><contrib contrib-type="author"><name><surname>Tatsunami</surname><given-names>Shinobu</given-names></name><xref ref-type="aff" rid="I4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Takenoshita-Nakaya</surname><given-names>Sachiko</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Harimoto</surname><given-names>Yoshie</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kinoshita</surname><given-names>Yuichi</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kobayashi</surname><given-names>Shinichi</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib></contrib-group><aff id="I1"><sup>1</sup>Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, Kanagawa 216-8511, Japan</aff><aff id="I2"><sup>2</sup>Institution for Animal Experimentation, St. Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan</aff><aff id="I3"><sup>3</sup>Department of Pharmacogenomics, St. Marianna University Graduate School of Medicine, Kawasaki, Kanagawa 216-8511, Japan</aff><aff id="I4"><sup>4</sup>Unit of Medical Statistics, Faculty of Medical Education and Culture, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan</aff><author-notes><corresp id="cor1">*Minoru Watanabe: <email>m4wata@marianna-u.ac.jp</email></corresp><fn fn-type="other"><p>Academic Editor: Phillip E. Klebba</p></fn></author-notes><pub-date pub-type="ppub"><year>2011</year></pub-date><pub-date pub-type="epub"><day>24</day><month>5</month><year>2011</year></pub-date><volume>2011</volume><elocation-id>502057</elocation-id><history><date date-type="received"><day>13</day><month>9</month><year>2010</year></date><date date-type="rev-recd"><day>25</day><month>2</month><year>2011</year></date><date date-type="accepted"><day>24</day><month>3</month><year>2011</year></date></history><permissions><copyright-statement>Copyright © 2011 Minoru Watanabe et al.</copyright-statement><copyright-year>2011</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>We investigated the effects of orange juice (OJ) or hesperidin, a component of OJ, on the pharmacokinetics of pravastatin (PRV) and the expression of both protein and mRNA of multidrug resistance-associated protein 2 (Mrp2) in the rat small intestine and liver. Eight-week-old male Sprague-Dawley rats were used in this study. OJ or a 0.079% hesperidin suspension was administered orally for 2 days. Tap water was given as a control. A single dose of PRV at 100 mg/kg p.o. was administered after 2 days of OJ, hesperidin, or tap water ingestion. The AUC, <italic>C</italic><sub>max</sub>, and <italic>t</italic><sub>1/2</sub> values of PRV were significantly increased in OJ group. Mrp2 protein and mRNA levels in the small intestine and liver, respectively, were significantly decreased after the ingestion of OJ. The same results were obtained with hesperidin. These results suggest that the changes in PRV pharmacokinetic parameters and the decrease in Mrp2 expression caused by OJ are due to hesperidin in the juice.</p></abstract></article-meta></front><floats-group><fig id="fig1" position="float"><label>Figure 1</label><caption><p>Effect of orange juice (OJ) on the plasma concentration of pravastatin (PRV) in Sprague-Dawley rats. OJ was administered orally 8 times (1st day) and 5 times (2nd day) at hourly intervals. The starting dose of OJ was 5 mL/kg, and each consecutive dose was 2.5 mL/kg. Tap water instead of OJ was given to the control group. A single dose of PRV at 100 mg/kg p.o. was administered 1 h after the last ingestion of OJ or tap water. PRV levels were measured using the HPLC method described in <xref ref-type="sec" rid="sec2">Section 2</xref>.</p></caption><graphic xlink:href="JBB2011-502057.001"></graphic></fig><fig id="fig2" position="float"><label>Figure 2</label><caption><p>Effect of orange juice (OJ) on Mrp2 protein levels in both the liver (a) and small intestine (b) in rats. OJ or tap water was given according to the same schedule as in <xref ref-type="fig" rid="fig1">Figure 1</xref>. The liver and small intestine were removed 1 h after the last ingestion of OJ or tap water, respectively, and plasma membrane fractions were prepared. Details of the Western blot analysis are described in <xref ref-type="sec" rid="sec2">Section 2</xref>.</p></caption><graphic xlink:href="JBB2011-502057.002"></graphic></fig><fig id="fig3" position="float"><label>Figure 3</label><caption><p>Effect of orange juice (OJ) on the expression of Mrp2 mRNA in both the liver (a) and small intestine (b) in rats. Tap water or OJ was given according to the same schedule as in <xref ref-type="fig" rid="fig1">Figure 1</xref>. The liver and small intestine were removed 1 h after the last ingestion of OJ or tap water, respectively, and total RNA was extracted from these tissues directly with the RNAgent Total RNA Isolation System. Levels of Mrp2 mRNA were determined with real-time PCR as described in <xref ref-type="sec" rid="sec2">Section 2</xref>.</p></caption><graphic xlink:href="JBB2011-502057.003"></graphic></fig><fig id="fig4" position="float"><label>Figure 4</label><caption><p>Effect of hesperidin (Hes) on the plasma concentration of pravastatin (PRV) in Sprague-Dawley rats. A hesperidin suspension was prepared at a concentration of 79 mg per 100 mL of tap water (0.079%). The suspension instead of OJ was given according to the same schedule and volume as in the OJ study (<xref ref-type="fig" rid="fig1">Figure 1</xref>).</p></caption><graphic xlink:href="JBB2011-502057.004"></graphic></fig><fig id="fig5" position="float"><label>Figure 5</label><caption><p>Effect of hesperidin on Mrp2 protein levels in both the liver (a) and small intestine (b) in rats. Hesperidin instead of OJ was given to 8-week-old male Sprague-Dawley rats according to the same schedule and volume as in the OJ study. Tap water was also given as a control. The hesperidin solution was prepared at a concentration of 79 mg per 100 mL of tap water. The small intestine and liver were removed 1 h after the last ingestion of hesperidin. Western blot analysis was performed using the same methods as in the in vitro OJ study.</p></caption><graphic xlink:href="JBB2011-502057.005"></graphic></fig><fig id="fig6" position="float"><label>Figure 6</label><caption><p>Effects of hesperidin on the expression of Mrp2 mRNA in both the liver (a) and small intestine (b) in rats. Determination of Mrp2 mRNA was performed using the same methods as in the in vitro OJ study.</p></caption><graphic xlink:href="JBB2011-502057.006"></graphic></fig><table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Effect of orange juice on the pharmacokinetic parameters of single-orally administrated pravastatin on rats.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2" colspan="1">Parameter</th><th align="center" rowspan="1" colspan="1">Control</th><th align="center" rowspan="1" colspan="1">Orange Juice</th><th align="center" rowspan="1" colspan="1">Ratio</th></tr><tr><th align="center" rowspan="1" colspan="1">(<italic>n</italic> = 6)</th><th align="center" rowspan="1" colspan="1">(<italic>n</italic> = 6)</th><th align="center" rowspan="1" colspan="1">(OJ/Cont) </th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><italic>C</italic><sub>max</sub> (ng/mL)</td><td align="center" rowspan="1" colspan="1">120.8 ± 17.2</td><td align="center" rowspan="1" colspan="1">161.4 ± 26.4*</td><td align="center" rowspan="1" colspan="1">1.34</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>T</italic><sub>max</sub> (min)</td><td align="center" rowspan="1" colspan="1">48.0 ± 12.5</td><td align="center" rowspan="1" colspan="1">50.0 ± 12.2</td><td align="center" rowspan="1" colspan="1"><bold>1.04</bold></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>t</italic><sub>1/2</sub> (min)</td><td align="center" rowspan="1" colspan="1">75.5 ± 18.4</td><td align="center" rowspan="1" colspan="1">138.8 ± 58.5*</td><td align="center" rowspan="1" colspan="1">1.84</td></tr><tr><td align="left" rowspan="1" colspan="1">CL/f (L/hr)</td><td align="center" rowspan="1" colspan="1">105.0 ± 22.8</td><td align="center" rowspan="1" colspan="1">49.0 ± 17.4**</td><td align="center" rowspan="1" colspan="1">0.47</td></tr><tr><td align="left" rowspan="1" colspan="1">AUC (ng·hr/mL)</td><td align="center" rowspan="1" colspan="1">207.1 ± 21.4</td><td align="center" rowspan="1" colspan="1">291.3 ± 78.0*</td><td align="center" rowspan="1" colspan="1"><bold>1.41</bold></td></tr></tbody></table><table-wrap-foot><fn><p>The data are expressed as the mean ± S.D. </p></fn><fn><p>*<italic>P</italic> < .05 and **<italic>P</italic> < .01, significantly different from control.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tab2" position="float"><label>Table 2</label><caption><p>Effect of hesperidin on the pharmacokinetic parameters of single-orally administrated pravastatin on rats.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2" colspan="1">Parameter</th><th align="center" rowspan="1" colspan="1">Control</th><th align="center" rowspan="1" colspan="1">Hespridin</th><th align="center" rowspan="1" colspan="1">Ratio</th></tr><tr><th align="center" rowspan="1" colspan="1">(<italic>n</italic> = 6)</th><th align="center" rowspan="1" colspan="1">(<italic>n</italic> = 6)</th><th align="center" rowspan="1" colspan="1">(Hes/Cont) </th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><italic>C</italic><sub>max</sub> (ng/mL)</td><td align="center" rowspan="1" colspan="1">116.5 ± 10.5</td><td align="center" rowspan="1" colspan="1">160.1 ± 20.7*</td><td align="center" rowspan="1" colspan="1">1.38</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>T</italic><sub>max</sub> (min)</td><td align="center" rowspan="1" colspan="1">52.5 ± 8.2</td><td align="center" rowspan="1" colspan="1">52.5 ± 12.6</td><td align="center" rowspan="1" colspan="1">1.00</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>t</italic><sub>1/2</sub> (min)</td><td align="center" rowspan="1" colspan="1">69.1 ± 3.7</td><td align="center" rowspan="1" colspan="1">140.3 ± 30.8*</td><td align="center" rowspan="1" colspan="1">2.03</td></tr><tr><td align="left" rowspan="1" colspan="1">CL/f (L/hr)</td><td align="center" rowspan="1" colspan="1">111.2 ± 44.4</td><td align="center" rowspan="1" colspan="1">55.9 ± 37.5*</td><td align="center" rowspan="1" colspan="1">0.55</td></tr><tr><td align="left" rowspan="1" colspan="1">AUC (ng·hr/mL)</td><td align="center" rowspan="1" colspan="1">213.5 ± 21.1</td><td align="center" rowspan="1" colspan="1">319.3 ± 23.7*</td><td align="center" rowspan="1" colspan="1">1.47</td></tr></tbody></table><table-wrap-foot><fn><p>The data are expressed as the mean ± S.D. </p></fn><fn><p>*<italic>P</italic> < .05, significantly different from control.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Japon</li></country></list><tree><noCountry><name sortKey="Kumai, Toshio" sort="Kumai, Toshio" uniqKey="Kumai T" first="Toshio" last="Kumai">Toshio Kumai</name><name sortKey="Tanaka, Masami" sort="Tanaka, Masami" uniqKey="Tanaka M" first="Masami" last="Tanaka">Masami Tanaka</name><name sortKey="Watanabe, Minoru" sort="Watanabe, Minoru" uniqKey="Watanabe M" first="Minoru" last="Watanabe">Minoru Watanabe</name></noCountry><country name="Japon"><noRegion><name sortKey="Matsumoto, Naoki" sort="Matsumoto, Naoki" uniqKey="Matsumoto N" first="Naoki" last="Matsumoto">Naoki Matsumoto</name></noRegion><name sortKey="Harimoto, Yoshie" sort="Harimoto, Yoshie" uniqKey="Harimoto Y" first="Yoshie" last="Harimoto">Yoshie Harimoto</name><name sortKey="Kinoshita, Yuichi" sort="Kinoshita, Yuichi" uniqKey="Kinoshita Y" first="Yuichi" last="Kinoshita">Yuichi Kinoshita</name><name sortKey="Kobayashi, Shinichi" sort="Kobayashi, Shinichi" uniqKey="Kobayashi S" first="Shinichi" last="Kobayashi">Shinichi Kobayashi</name><name sortKey="Takeba, Yuko" sort="Takeba, Yuko" uniqKey="Takeba Y" first="Yuko" last="Takeba">Yuko Takeba</name><name sortKey="Takenoshita Nakaya, Sachiko" sort="Takenoshita Nakaya, Sachiko" uniqKey="Takenoshita Nakaya S" first="Sachiko" last="Takenoshita-Nakaya">Sachiko Takenoshita-Nakaya</name><name sortKey="Tatsunami, 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