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� � ��������� Vol. 33, pp. 455�466, 2005
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� �'()*+,)-./0�1�23456789:;<.=>?@AB� CD� EFG4HA@IJK+,)- �Citrus Unshiu� .�LMNO�PEQ-RS� �PRV� 100 mg�kg� 1�MT234 UB564VA@WXYZ� �[@\])P'()*+,)-1564VA@^WXYZ� _>4IJK+,)-1`##�abB flavanones 1 hesperetin <hesperidin 4cB PRV 1�23d1564VA@^WXYZ� 2�e 8f�1�g SD hEFG7�AZ� IJK+,)-� \])P'()*+,)-< flavanonese� PRVi 15�j4 5 ml�kg� PRVi k� Hcli 20 � 30��4 2.5 ml�kg7m?n?opi YZ�PRV1MTqre HPLC �as�YZ� IJK+,)-e PRV 1MTqrktuvw�x�AUC0�2.5h� y7�z{|_[� }MTqr �Cmax� y^�z{|_[Z� !�� }MTqr~�kt �tmax�<��� �t1�2�4�z���e�J�Z� Hesperetin< hesperidin �250 mg�kg�^��4 PRV 1 AUC0-2.5hy7�z{|_[� Cmax y^�z{|_[Z� !�� tmax< t1�2 4�z���e�J�Z� �Z� \])P'()*+,)-e PRV 1������4�z�567 U�J�Z� �{1��� IJK+,)-� hesperetin < hesperidin eopi YZPRV 1������7��_[B;<7�>J4YZ�
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���������� ���� �����P450 �CYP�������� CYP3A4� PRV��������������� �!""6��Lilja ��� #$�%&'�()*�+� PRV� AUC� ,�-� �Cmax�� ,�-�� ./ �tmax� ��01 �t1�2� ��234�56�"��7�� 7�� #$�%&'�()*�+�8����9:���#$�%&'�()*�+�naringin; furanocoumarins, bergamottin, bergap-ten, 6’ -epoxybergamottin, 6’ 7’ -dihydroxyberga-
mottin ��<��=��!"�>��?@��!"�8��� A�B��������#$�%&'�()*�+�34�56�">��� �C� 8D<�� PRV �������E�34�F"G��HE���� ,I� JK���LMN�� flavonoids� 1���� flavanone� hespere-tin � hesperidin �OP�QR9�10�� OS�QR11��T�!-UV�WQR12���X��:��YZ>��?@��!"�� >�� flavanones �[��� ��L!\���G�� �&]^_^`�a"!� 1"# b hesperetin !\�� 28.3 mg�$ flavonoids � 51��� ��13�� cN��Nb%&�de!>f � >� e�>�� fl-avanones �g����������E�34�'��"(���"� hij�� hesperetin� hesperidin �� flavanones ��LM�k�>��)��!"�14�16�� N #$�%&'�()*�+�8����9:��lm��L��!"��� *�&'�()*�+�n$^))*�+;j�)*�+��8����9:��lm��L�"� T>�co� PRV �������E�flavanones��LM�k�hij��pq+�k�j�)*�+� flavanones �34�'��k� e� j�)*�+�T�r<<����hesperetin � hesperidin � PRV ������E�34�Z"!s,� �
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2�� /z�z�34�|}������lm�5���� � a� /lm�|��/z|}����{�8���� �6��67� 0508001����!"���� �� ���� flavanones� �������� ���� PRV �����
|}8����A �A9A� n 9�� j�)*�+:�����hij�+�$��)*�+ �Citrus Unshiu�� ��{�������%� �;� �n6� �� hesperetin :�� �n6� �� hes-peretin �250 mg�kg, 20 mg�mlA9A���� SigmaChemical, St. Louis, MO, USA�� hesperidin :�� �n6� �� hesperidin �250 mg�kg, 20 mg�ml A9A���� Sigma Chemical�� #$�%&'�()*�+:�� �n5� ��#$�%&'�()*�+�100� �� ��¡¢�£#$�%&'�()*�+� ¤¥^¦§$v)�� <¨��T�©�:�� � j�)*�+�#$�%&'�()*�+�:���:�+ª)*�'� Dresser���717��«¬!� hesperetin � hesperidin �:��� Kim �18���7�a��:���� :�+ª)*�'� Dresser ���717��«¬!�f �PRV � 100 mg�kg �=o®:�� � j�)*�+� flavanones a8¯#$�%&'�()*�+�>��:�+ª)*�'�� N° PRV:� 15��� 5 ml�kg®:��� PRV 100 mg�kg� 2.5 ml�kg� PRV:�.� a8¯:� 20� 30�±� 2.5 ml�kg�j�)*�+� flavanones ��"�#$�%&'�()*�+�T�©�®:�� � ?@-� 20 ml� 0.2 M EDTA �A� *�²� PRV:� 5� 10� 15� 20� 30� 45� 60�75� 90� 120� 150 �±�³-� � -B��C��PRV �DE�F´��" � >��:�+ª)*�'� Fig. 1 �?� ��� PRV ����i� HPLC �8� PRV �DEPRV�DEG� Otter � Mignat19� � Iacona �20�
��7�µH��!�f � �(H«� methanol���� triamcinolone acetonide �Sigma Chemi-cal� �x�� � �(H«�¶�� 1 mg�ml �:<�� _v��-B 100 ml � 300 ml ·E� ���IJA 900 ml�·E¸K� � s�� C18 prepara-tory solid-phase extraction column �Sep-Pak car-tridge, Waters Co., Milford, MA, USA� �L� �
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�� column � 2 ml � methanol ���� 60�� ������ ���� ��� 300 ml �methanol ����� ���� 100 ml� HPLC ������ HPLC � DP-8020 ���� AS-8020� !"��� �UV��# �UV-8020�! $ %&'(� )*� +,-./0123� 4� cos-mosil 5C18-AR column �5 mm particle size, 4.6�150nm ID, Nakalai Tesque, *5� �67�� PRV �8��9�:;<�=.� 74� anmonium phos-phate �0.05 M, pH 3.50�� 26� acetonitrile �>7�� ?@� 1.0 ml�min �A�B�CD� 37�C �>7�� UV EF� 240 nm �GH��� PRV IJKLM�>3 triamcinolone acetonide �NOP��0Q0 13I 23�>7�� PRV �GHRS� 10 pg�ml�500 ng�ml�>7��ii� T U �8PRV �VWXDPT U ��8��� PRV
IJKLM�>3 triamcinolone acetonide �Y Z�T U � LC-8020 multistation system �! $ %&'(� �[\Y Z]^_��8��triamcinolone acetonide �`ab+, PRV �`ac�de�1VW PRV XD�e������ ����H� StatView �Ver. 4.58� Abacus, Berkeley,
CA, USA� �f2167�� gh;ij�k U � 2 way ANOVA �� Sche#e _l�m� Mann
Whitney-U �H_�1ndopqrs��H���tuc� 5� vw�qrx>\IyH��� T U �z{|�LM}x�~���
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�� ��� � PRV ��������������������� �!�"# �Fig.2$ Table 1�
Fig. 2 ����[������ �+��� ����Il� PRV ���� PRV �VWXD��Pp����� ��� 45�Y Z���� ������������ �+��� �� PRV �AUC0�2.5h|�qr���/� �� 340�� ���AUC0-2.5h: 122.5�14.9 ng�hr�ml vs �+��� ���� AUC0-2.5h: 416.9�58.1 ng�hr�ml� p0.05����VWXD �Cmax� |lqr���/�� ��280�� ��� Cmax: 120.1�36.1 ng�ml vs �+��� ���� Cmax: 337.9�22.7 ng �ml� p0.05�� ��� ��VWXD��P �tmax� I����t1�2� �qr�� �¡9�+7����� tmax: 42.0�6.3 vs �+��� ���� tmax: 48.0�13.4� ��� t1�2: 47.2�12.3 vs �+��� ���� t1�2: 38.5�4.9���� ��� � PRV ����������������� hesperetin �"# �Fig. 3$Table 2�
Fig. 3 ����[������ hesperetin ���Il� PRV ���� PRV �VWXD��Pp����� ��� 30 �Y Z���� ������������ Hesperetin � PRV � AUC0�2.5h
|�qr���/� �� 300�� AUC0�2.5h: 352.1�41.2 ng�hr�ml� p0.05�� Cmax |lqr���/�� �� 320�� Cmax: 388.7�66.3 ng�ml� p
Fig. 1. Time schedule of citrus juice, hesperetin, hesperidin, grapefruit juice, water, and
pravastatin �PRV� administration and blood collection.
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0.05�� ��� tmax� t1�2������ �����tmax: 37.5�7.8�� t1�2: 48.1�16.4����� ������ PRV �� ������������ hesperidin �� �Fig. 4�Table 3�
Fig. 4 ����������� hesperidin ������ PRV ���� PRV ��� !"#$%�&'�� ��� 30 �()*+�,�� -./.
0��12��� Hesperidin " PRV � AUC0�2.5h3����4567 �8 400�� AUC0�2.5h: 487.0�88.2 ng�hr�ml� p�0.05�� Cmax 3����&'67� �8 290�� Cmax: 352.1�49.4 ng�ml� p�0.05�� ��� tmax � t1�2 ������ ���� �tmax: 48.3�13.3�� t1�2: 44.4�10.1����� ������ PRV �� �������������������� !�"
Fig. 2. E#ects of citrus juice on the pharmacokinetics of orally administered pravastatin
�PRV� in the plasma of rats. Mean plasma PRV concentration-versus-time profilesafter a single dose of PRV 100 mg�kg p.o. with citrus juice �n6, circles� or water�as a control, n9, squares� are shown. Citrus juice significantly increased the areaunder the curve �AUC0�2,5h� and maximum concentration �Cmax� of PRV in rats.Citrus juice had no e#ects on the tmax and t1�2 of PRV in rats. Data are expressed as
mean�SEM.
Table 1. E#ect of citrus juice on the pharmacokinetics parameters of pravastatin �PRV,100 mg�kg� in plasma of rats.
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��� �Fig. 5� Table 4�Fig. 5 ��������� �� ��� �
�� ������ PRV ���� PRV ������ !"�#$�� ��� 30%&' (�)�� *+,+-��./��� �� ��� ��� �� PRV � AUC0�2.5h �114.9�7.7 ng�hr�ml�� Cmax 0 �129.4�15.6 ng�ml�� tmax �48.7�7.2%�� t1�2 �47.1�12.1%��123456�7389
��
� �
:;�<=&�>?@�ABCD8E�� �FGH PRV� AUC� Cmax0612�IJKLMN�6�OPCQR8���� ST� D8E�� �� PRV ���8R�UV�(WX>Y���456�73BN�6QR8���� Z�� D8E
Fig. 3. E#ects of hesperetin on the pharmacokinetics of orally administered pravastatin
�PRV� in the plasma of rats. Mean plasma PRV concentration-versus-time profilesafter a single dose of PRV 100 mg�kg p.o. with hesperetin �n6, circles� or water�as a control, n9, squares� are shown. Hesperetin significantly increased the areaunder the curve �AUC0�2,5h� and maximum concentration �Cmax� of PRV in rats.Hesperetin had no e#ects on the tmax and t1�2 of PRV in rats. Data are expressed as
mean�SEM.
Table 2. E#ect of hesperetin on the pharmacokinetics parameters of pravastatin �PRV,100 mg�kg� in plasma of rats.
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��������� � flavanones � hes-peretin � hesperidin ������������PRV�AUC� Cmax��������� PRV��� !"�#$%&�'()*+��,�-��./� 01�234�5����$ PRV �6789:!;�<�#%&�'()�=��>?�@AB�CDEFG#H*IJKL67�MN#$O!"�P�<��Q'RI*�+��STRI*�21�� UV� !WO#H*I������
�� PRV� AUC� Cmax������� 67�XYZ[\]���#$O!"�P�<�E67^_`a�%&�b(c-�� >?�67$ CYP �^_�-�+��dc-I*�� R�R)�c�PRV$JKL67� ��e� PRV�67fg89#$ CYP3A3hi���$je�k�67^_`a�%&$l��m)*+��ST�-I*�6�7�� +��e� UVnec-��������#o� PRV� AUC� Cmax��pq#rk�CD
Fig. 4. E#ects of hesperidin on the pharmacokinetics of orally administered pravastatin
�PRV� in the plasma of rats. Mean plasma PRV concentration-versus-time profilesafter a single dose of PRV 100 mg�kg p.o. with hesperidin �n�6, circles� or water�as a control, n�9, squares� are shown. Hesperidin significantly increased the areaunder the curve �AUC0�2,5h� and maximum concentration �Cmax� of PRV in rats.Hesperidin had no e#ects on the tmax and t1�2 of PRV in rats. Data are expressed as
mean�SEM.
Table 3. E#ect of hesperidin on the pharmacokinetics parameters of pravastatin �PRV,100 mg�kg� in plasma of rats.
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���� CYP ������ ����������������� PRV� AUC Cmax����� !"#$%� 2&�'()*������ 1� �������*���+,� PRV �-./012�34� 2� �������*567�PRV �89:�/;<2�34� =>� �������� PRV �?@ABC���DE ��/F� �GH� I"�������*567�PRV �89:�/;<2� PRV �?@ABC��J%2������� K�K��� =>�
���������� PRV� AUC Cmax������56L� PRV 89:��;<L� M����+,� PRV -.�01��*NO"#��'()*���������+�#�PQR��ST7�UV�WX�� organic anion transporter polypeptides � YL�OATPs� BZ[L� oatps\]�� ATP bindingcassette �ABC� transporters *^_ `a/�H"#��K*b��#��22�� ���+,� PRV�cd -.efghi�jk�Klm��L� �� "�" *�56�+�# PRV � oatp1�
Fig. 5. E#ects of grapefruit juice on the pharmacokinetics of orally administered
pravastatin �PRV� in the plasma of rats. Mean plasma PRV concentration-versus-time profiles after a single dose of PRV 100 mg�kg p.o. with grapefruit juice �n�5,circles� or water �as a control, n�9, squares� are shown. Grapefruit juice had noe#ects on these pharmacokinetics parameters. Data are expressed as mean�SEM.
Table 4. E#ect of grapefruit juice on the pharmacokinetics parameters of pravastatin
�PRV, 100 mg�kg� in plasma of rats.
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oatp2����������� ������������23�24�� ����� oatp2 � oatp3 ����� !"#�$%&���'����(����25�� PRV �)* +,� oatp1� oatp2 -.�/�'��0����21�� �� �����1�� OATP 23456��! !"#���7 �8�9:����� ;<� ;=>�?@�ABC6D��� PRV AUC� CmaxEFGH�1I��� oatp2 9��J��K &?��LM6N2O6PBC6D�QR�STU�VW'&�� �X�YZG�[\V�]�'��^*0����� ��LM6N2O6PBC6D��� _`V�! ab��cd�CYP3A4 Z P �e� fgV�c&�h�g ij����VEF(k�'����(����2�3�� LM6N2O6PBC6D��� CYP3A4�cGH��LM6N2O6PBC6DX fl-avonoids �9�&���'��lm(����8��LM6N2O6PBC6D���STU� �>�n�LM6N2O6PBC6D�o�pq��� naringin �9r&������(�?26�27�� (�s tuu� �furanocoumarins, bergamottin,bergapten, 6’ -epoxybergamottin, 6’ 7’ -dihydroxy-
bergamottin� v CYP3A4 fgV�cd�'��w(�?28��32�� ;=� Lilja 7� ����� LM6N2O6PBC6D� PRV �Y� x/[\V�]/��?� ' '��� y/*�v'�LM6N2O6P�STU��9rd�'��wz(�?u�� PRV �Y��[\V�]/��{]��� |!� Dresser 17������oatp ��� fexofenadine � �@V furanocou-marins ��cd�'�V��&���� Bailey32�� 6’7’-dihydroxybergamottin ���� oatp1
}~�/�'�V��&���� �?� Mal-hotra 33�� bergamottin Z 5-methoxypsoralen ���� oatp1V:���}~d�'�V��&���� v&� @�ABC6DX '� flavonoids� PRV ��� _`�9r&��� oatp fgV}~d�/�� PRV AUC � Cmax ��yd�v �{]��� (� Dresser 17���M�BBC6DX��'�tuu��LM6N2O6PBC6D�"� 5� 150� 1�p&�q����/����&���� ;=��?@�A
BC6DX flavonoids +u�q#�$���/�� &�&/�LM6N2O6PBC6D�PRV �Y� x/[\V�]�� @�ABC6D� PRV AUC� Cmax EFGH�>�?'��� y/*�v;= ���%��?@�ABC6D��� PRV AUC EFGH ������ flavonoids [\�y/��&g�{]���Hesperetin � hesperidin ���'�)*q��
� flavanone ���� ��� '� flavanone ���(GH9�10�� ���GH11�� �&��Xh.��GH12�/�)�/i)U�V�J'��wz(����� �'�;=� PRV AUC EFGH�9rd�@�ABC6D u�V$��d�?��hesperetin � hesperidin PRV �X�Y��]�[\�J��K &?� � �H� @�ABC6D�� hesperetin � hesperidin � PRV AUC � Cmax VEF(k?��5���D��[\V�]/��?� ' �H�y/*�v@�ABC6D��� PRV AUC EFGH |*�hesperetin� hesperidin�9r&����&gVwz&���v �{]����M�BBC6D��< hesperetin ���X�p+ ¡¢� 6¡¢���13�� ' ?�� ;=PRV ,� 15�£� ,��¡¤� 20�<� 30�<�@�ABC6DV��&�v� �X7 hespere-tin _`� PRV tmax ¡¥��:������{]��� PRV �5���D�¦�/��?'��� '� �HV§:k�{]��� ;=@�ABC6D��� PRV �X�Y -�v�X�_`(�? hesperetin Z hesperidin ���[\� v� ¨�v©�?��� PRV �!� _`ª��1I� hesperetin Z hesperidin STU��«¬����&g�{]��� Ka-waii �®@�AX u� 24R'�J���¯&� hesperidin � 1596 mg�100 mg ��v)*q��� °� narirutin 61 mg�100 mg� neoponcirin 35mg�100 mg ±�q (����'�V��&��� �hesperetin �K (���/��34�� ;<� '� hesperetin Z hesperidin ²³ u� �&g�J��vK d�./����´:���;=� ����@�ABC6D� PRV AUC1�µ Cmax V��¶� 340� � 280� ��EFd�'�V$��&?� PRV �oh�· ¸¹
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��������� �� ������������������ !"#$%&'� �()*��+�,'-./0��������1234%567�89� :;��<=>%?@A��� BC�DE�FGHA PRV ���IJK� �LM%NHOPQR�IST�UV7WK�X� PRV�1234%567�Y4�12Z[�\]R^_`�a� !"#��+����%bcd�ef>%gh��� �� flavanone i12�jk_`��&�lX%mn�� �12�� l��o� flavanone � PRV � AUC %pqd�rK��s� flavanone tu�12jk_`�%c���v%pSd�ef>%?@A��� Bw� xy��UVd�T�NHOPQR��,� PRV ��(z{�|@�}~�� ���7�� 5��ef>�� ��u����7� s��>%&�X������5�FG� NHOPQR�� hesperetin X hes-peridin i���|7� PRV ��u���Ipq/�lXI�AH�7�� BwiA��PRV ���Y���K������R�RXNHOPQR�a hesperetin� hesperidin X�)*���7����DEId���&�X?@��
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Abstract
E#ect of Citrus Juice on the Bioavailability of Pravastatin in Rats.
Yu Koitabashi, Toshio Kumai, Jiro Kogo, Takahiro Amamoto,
Yoshimitsu Tsuzuki, Naoki Matsumoto, and Shinichi Kobayashi
Our objective was to investigate the e#ects of citrus juice �Citrus Unshiu� on the pharmacokinetics ofpravastatin in rats. The pharmacokinetics of pravastatin �PRV, 100 mg�kg, p.o.� were assessed with water,citrus juice, grape fruit juice, hesperetin, and hesperidin �250 mg�kg over 30 min�. Male 8-week-old Sprague-Dawley �SD� rats were used. The volume and schedule of fluid �water, citrus juice, grapefruit juice,hesperetin, hesperidin� intake were 5 ml�kg 15 min before PRV administration, 2.5 ml�kg with PRV 100mg�kg and 2.5 ml�kg after 20 and 30 min, respectively. Venous blood samples were placed in tubescontaining 5 ml of 0.2 M EDTA 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, and 150 min after administration to
measure plasma PRV concentrations. PRV levels in plasma were measured by HPLC. Citrus juice
significantly increased the area under the curve �AUC0�2,5h� and maximum concentration �Cmax� of PRV inrats. Citrus juice had no e#ects on the time to reach Cmax �tmax� and half life of PRV �t1�2� of PRV in rats.Hesperetin and hesperidin significantly increased the AUC0�2,5h and Cmax of PRV in rats. Hesperetin and
hesperidin had no e#ects on the tmax and t1�2 of PRV in rats. On the other hand, grapefruit juice had no e#ectson these pharmacokinetics parameters. In conclusion, citrus juice increases the bioavailability of PRV
administered orally.
Key words
HMG-CoA reductase inhibitor, citrus juice, bioavailability, rats, drug interaction,
drug transporter, intestine
Department of Pharmacology, St Marianna University School of Medicine
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