12
臖腽膂腫膅腷膈膒臣膖膷膹 Vol. 33, pp. 455466, 2005 腅腂腈腉腏腀腊腃腆腇腕腖腔腘腗腟腝腎腐腍腊腋腌腑腄 腝腜腔腚腛腙腃腞腁腇腒腓 腅腏 腕腍 腛腆 腊腗 腓腍 腋腆 腝腆 腄腗 腙腓 腏腈 腖腝 腒腉 腜腍 腘腑 腗腑 腙腓 腔腇 腋腕腚腍 腍腞 腅腐 : 17 10 21 腺膃腀腴腯膀腀腰腇膕臁腒腄腒腄臲臡腙膌膟腩膝腟腍腊腖腇臦腤腧腔腂腦膴膔膁腳腵 腙腅腂腔腡腆腪腯膀腀腰 Citrus Unshiu腇膲膸膦臋膼腟腒腻膁腹腰腱腲膅 PRV100 mgkg腒腄膦臨臲臡腙腄腦膌膟腙腓腂腔膨臱腌腑腎腔腮膄腀腻腺膃腀腴腯膀腀腰腚膌膟 腙腓腂腔腢膨臱腌腑腋腤腙腡腆腪腯膀腀腰腚膰臔臔腕腁腦 flavanones hesperetin hesperidin 腙腣腦 PRV 腒腄臲臡腝腚膌膟腙腓腂腔腢膨臱腌腑8 SD 膁腳腵腩腂腑腡腆腪腯膀腀腰腮膄腀腻腺膃腀腴腯膀腀腰腖 flavanones PRV 15 臚腙 5 mlkgPRV 腅腣腜臯20 30 膬腙 2.5 mlkg 腩腏腧腐腧膤膮臯腌腑PRV 腚膦臨臹臮腛 HPLC 腕自腌腑腡腆腪腯膀腀腰腛 PRV 腚膦臨臹臮膻膛膠臙膏AUC02.5h臥腩膇臍臉腋腎膵臣膦臨臹臮 Cmax臥腢膇臍臉腋腎腑膵臣膦臨臹 臮臰臤膻膛 tmax腖臻膩膜 t12膇腘膐腛腘腆腒腑Hesperetin hesperidin 250 mgkg腢至PRV AUC0-2.5h臥腩膇臍臉腋腎Cmax 臥腢膇臍臉腋腎腑tmaxt12 膇腘膐腛腘腆腒腑腠腑腮膄腀腻腺膃腀腴腯膀腀腰腛 PRV 腚臕臟致腜腙腞膇腘膌 膟腩腄腘腆腒腑膆臍腚膥膓腡腆腪腯膀腀腰hesperetin hesperidin 腛膤膮臯腌腑 PRV 腚臕臟致腜腙腞腩臝膑腋腎腦腊腖腩腤腆腙腌腑ῐῌ῏ 膲膸膦臋膼腟腒腡腆腪腯膀腀腰臕臟致腜腙腞腒腄臜膫膶腺膁腼腸腬腶 腺膃腀腴腯膀腀腰腇膕臁腒腄腒腄臲臡腙膌膟腩 膝腟腍腊腖腇臦腤腧腔腂腦腮膄腀腻腺膃腀腴 腯膀腀腰腩膋腍腦腖 felodipine 腚膦臨臹臮膻膛膠 臙膏AUC3 臺臝膑腋腎腑腖 Bailey 11991 臸腙膳腌腔膆腮膄腀腻腺膃腀腴腯膀腀 腰腇 CYP3A4 臒腍腦腊腖腕腒腄腚臕 臟致腜腙腞膐腋腎腦腖腂腃膳腇臞腈腘腋腧腔 腂腦 23腌腆腌腘腇腤臑腒腄腙臠腍腦腺膃腀 腴腯膀腀腰腚膌膟腛腞腖腪腗膳腋腧腔腂腘腂膲膸膦臋膼腟腒腕腁腦3-hydroxy-3-methylglu- taryl coenzyme A HMG-CoAreductase inhibitors 腰腱腲膅膗臲膽膙腩膇腙膩臈腋腎腦腊腖 腕臎膦膚膺臌腚臒腙臐臆腋腧腔腂腦 4HMG- CoA reductase inhibitor 腕腁腦腻膁腹腰腱腲膅 PRVactive hydroxy acid form 腚腷腵膂腭腾膍 腕腁腥膤膮臘臀腙腅腉腦臕臟致腜腙腞20腖膪腨腧腔腂腦 5腠腑 PRV 腛膱臛臫膝腜膱臛 臫臼膎腕腂腈腓腆腚臢膾膐腌膿腙臷臨腙臖腽膂腫膅腷膈膒臣膖 腒腝455 99

˘ˇ ˆ ˙˝˛ ˚˜ ! - Marianna Uigakukai.marianna-u.ac.jp/idaishi/www/335/12-33-5Yu..." T>co PRV ˘ˇ E flavanones ˜˙LM khij ˝˜pq +˙k j ˝)* +˙ flavanones 34˜’ ˇ k

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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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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

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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�

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|�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

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:;�<=&�>?@�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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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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