全 文 ：中草药ChineseTraditionalandHerbalDrugs第36卷第11期2005年11月
PharmacokineticsofaristolochieacidAinRadixAristolochiae
andGuanxinsuheCapsule
TIANBao—pin91～·ZHANGLan～ton91，YUANZhi—fan91，LIUWei—nal’LIUHong—jul
(1．DepartmentofPharmaceuticalAnalysis，SchoolofP armacy，HebeiMedicalUniversity，Shijiazhuang050017，China
2．InstituteofMilitaryMedicinetLogisticsDepartmentofHeadquarterofGeneralEquipment，Beijing100101，China)
Abstract：ObjectiveTostudythepharmaeokineticsofaristolochicacidAinRadixAristolochiaeand
thecompoundpreparationofGuanxinsuheCapsuleinmiceinvivoaftersingle—doseoraladministrationand
observethdifferenceofaristolochica idAabsorptionandistribution．MethodsAristolochicacidA
assaywasperformedbyRP—HPLConaWatersapparatuswitha DiamonsilTMC18column(250mm×4．6
mm，5Ⅲn)，amobilphase{amixtureofm thanol—water—aceticacid(72I 27l 1)，flowrate：1．0mL／
min，detectionwavelength：315nm，andcolumntemperature：20℃．ResultsMiceweregivenRadix
AristolochiaeandGuanxinsuheCapsulebyigatthesamel velof2．5mg／kgofaristolochicacidA，respec—
tively，whicheresuspendedin0．3％CMC—Nasolution．PlasmaconcentrationsweredeterminedbyRP—
HPLC．Aftersingle—doseigadministrationofRadixAristolochiaerGu nxinsuheCapsuletomice，the
meanplasmaconcentration—timec ursesofaristolochicacidAobtainedfittedtheone—compartmentmodel．
Themainpharmacokineticparametersofa istolochiea idAinRadixAristolochiae，tl／2k。，tll2k，☆。。，
AUC，c。：are5．103rain，43．63rain，17．89min·80．45(pg·min)／mL，and0．9168／19／mL；therela—
tivepharmacokinetieparametersinGuanxinsuheCapsulear5．294min，43．50min，18．32min，33．08
(腿·min)／mL，and0．3818vg／mL．ConclusionTheG。。ofaristolochicacidAinGuanxinsuheCapsule
issignificantlylesshanthatinRadixAristolochiae，whichindicatesthatthecompoundcompabilitycould
decreasetheabsorptionofaristolochiaea idA．
Keywords：aristolochicacidA；pharmaeokinetics；RadixAr stolochiae，GuanxinsuheCapsule
青木香和冠心苏合胶囊中马兜铃酸A的药动学研究
田葆萍“2，张兰桐”，袁志芳1，刘伟娜1，刘红菊1
(1．河北医科大学药学院药物分析教研室，河北石家庄050017；2．总装备部后勤部军事医学研究所，北京100101)
摘要t目的研究青术香及复方制剂冠心苏台胶囊中马兜铃酸A在小鼠体内的药动学特点及小鼠在ig给予古
相同量马兜铃酸A的青木香和冠心苏台胶囊后，马兜铃酸A的吸收、分布规律的差异。方法采用RP—HPLC法测
定血浆中马兜铃酸A的量。色谱条件，色谱柱为DiamonsilTMC。。柱(250mm×4．6mm，5pm)，流动相为甲醇一水一
冰醋酸(72—27t1)，体积流量为1．0mL／min．检测波长为315um，柱温为20℃。结果药动学实验结果显示小
鼠分别ig给予青术香和冠心苏合胶囊(相当于2．5mg／kg马兜铃酸A)后，其体内的药动学房室模型均符合一室
模型，青木香中马兜铃酸A主要药动学参数ttjnh、tl／2h．f⋯Auc、c一分别为5-103rain、43．63rain、17．89min、
80．45(¨g·min)／mL、0．9168pg／mLI冠心苏合胶囊中相应的参数分别为5．294rain、43．50min、18．32rain、
33．08(ug·min)／mL、0．3818pg／mL。绪论小鼠给予含马兜铃酸A相同剂量的青术香和麓心苏合胶囊后，冠心
苏舍胶囊中马兜铃酸A的cm；明显低于青木香中的c～，说明复方配伍作用可减少马兜铃酸A的吸收。
关键词：马兜铃酸A，药动学}青术香，冠心苏台胶囊
中圈分类号：R285．61 文献标识码：A 文章编号t0253—2670(2005)11—1671—04
AristolochicacidA，achemicalonstituentxistinginthespeciesofAristolochiaL．andsome
鉴墓最留：篙；2晷螽臻技术研究计划项目(。32，。1。6D-：)
譬翥甍器薯8蔫蓬描76看鼻％：紧庄86人265’硕63士5研F究ax生：’(0主3要11}fi嚣魏蠹+{嘿挚!：芒磊；。。。@。。。．。。。
万方数据
·1672· 中草药ChineseTraditionalandHerbalDrugs第36卷第11期2005年11月
Asarumspeciesh rbs，wastheimpetusbehindthe
FDAimportalertinMay．2000．Thisalertcalled
forthe“detainmentwithoutphysicalinspection，of
herbssuspectedtob composed，inwholeorpart，
ofanyspeciesofAristolochiaL．，orotherherbs
thatmaybesubstitutedforit，’[11．Aristolochicacid
Aiscommonlyfoundinmedicinalpl ntssuchas
AfistolochiadebilisS eb．etZucc．whichasbeen
reportedtocauser nalfailure．
GuanxinsuheCapsuleiscomposedofStyrax
(LiquidambarorientalisMill．)，LighumSantali
^lbi(SantalumalbumL．)，删iba2zum(Boszoellia
carteriiBirdw．)，BorneolumSyntheticum(bor—
ne01)andRadixAristolochiae(Aristolochiadeb lis
Sieb．etZucc．)whichcontainsaristolochicacidA．
Itjsa traditiona】Chinesecompoundm dicineand
hasbeenusedasacardiovasculafmedicinefors v—
eraIhundredy ars[“．Theaimofthisstudywasto
investigatethepharmaeokineticsofaristolochic
acidAinRadixArlstoi’ochiaeandGuanxinsuhe
Capsuleaftero aladministration．
1 Materials
1．1 Chemicalsandreagents：AristolochicacidA
referencesubstancewasboughtfromNationalIn—
stitutefortheControlofPharmaceuticalandBio—
logicalProducts，LotNo．：746—9002．RadixAris
tolochiaewanpurchasedfrommarketandidentified
byProfessorNieFeng—zhi．GuanxinsuheCapsule
waspurchasedfrommarket(Manufacturer：The
FifthP armacyofChineseTraditionalMedicinein
Tianjin，LotNo．：000633)．Methanolusedwas
HPLCgrade．Aceticacidusedwasanalytical
grade．WaterusedforHPLCwasultrapurewater．
1．2 Animals：Kunmingmice(早and0，z5—30
g)werepurchasedfromExperimentalAnimalCen—
terofHebeiMedicalUniversity．Allmicewere
keptinanenvironmentallycontrolledbr eding
room[temperature：(24土1)℃，humidity：(60士
5)％]foroneweek，andtheydrankfreelybut
werenotfed15hbeforethexperiment．
1．3 Apparatus：Thehighperformanceliquid
chromatographicsystemwasequippedwiththe
pump(Waters515，USA)andanultravioletde—
tector(Watersmod l2487，Milford，Massachu—
setts，USA)andaClBcolumn(250mm×4．6mm，
5“m)．AnequilibratingmodelrecorderN一2000
wastheproductofZhejiangUniversity，China．
2 Methodsandresults
2．1 Standardsolution：Anaccuratelyw ighed
quantityofaristolochicacidAwastransferredtoa
10mLvolumetricflaskontainingmethanolto
obtaina finalconcentrationof0．183mg／mL
solution．Thispreparedsolutionwastoredat
about4℃．
2．2 Chromatographicconditionforaristolochic
acidA：Afew(20pL)oftheplasmasamplesw re
injectedintochromatographandthepeakresponse
valueofaristolochicacidAwasmeasured．There
wasnodetectableendogenousmaterialintheplas—
mainterferingw ththedeterminationofaris—
tolochicacidA．Mobilephase：methanol—water—
acetica id(74l 27I 1)，flowrate：1．0mL／min，
columntemperature：20℃，anddetectionwave—
length：315nmwith0．5absorbanceunitsfull
scale(AUFS)．Chromatographreplicatedinj c—
tionsofthestandardsolutionsandrecordedthe
peakresponsesa directedun erp ocedure：the
relativestandarddeviationwaslesathan4．0％and
thetailingfactorforaristolochicacidApeakisless
than1．20．Theretentionmeofaristolochicacid
Awasapproximately16min(Fig．1)．
2．3 Calibration：Thestandardsolutionwasdilut—
edwithmethanoltomakea seriesofsolutions
between0．1098 and36．6gg／mL．Dilutions
(0．6mL)wastransferredto0．2mLblankplas—
ma．After10svortexand10raincentrifugationat
3000×g。thesupernatantwasfiltratedwithfilter
(0．45pm)andthen20pLofthefilteredsampe
wasinjectedforHPLCanalysis．Thetandard
curveshoweda goodlinearityovera rangeof
0．1098—36．6pg／mLforaristolochicacidA(y一
13．723X+0．1 9，r=0．9996，whereyandXin—
dicatethearistolochicacidAchromatographicpe k
areaandplasmaconcentration，respectively)．
2．4 Recovery：Themeanrecoveryofaristolochic
acidAfromicewas97．0％，99．4％，and
101．4oA(m一5)athigh，medium，andlowconcen—
tr tions(1．830，0．366，and0．1098ttg／mL)with
万方数据
中草药ChineseTraditionalandHerbalDrugs第36卷第11期2005年11月· 673·
0 5 10 15 20 rj—1矿1ijo矿丁1015 20 0 5 10 15 20
t／min
*一aristoloehicacidA
A—blankplasmaI}blankplasmasamplespikedwithstandardarlstotoehicacidA
C—mice’splasmaampleofRadixAristolochlcaeD-mice
7
Bp asmasampleofGuanxinsuheCapsule
Fig．1Chromatogramsofa lstolochleacidA
theRSDat1．4％，0．8％，and2．4％(”=5)．
2．5 Determinationofmethodprecsion：Theco—
efficientofvariationforanalysisinplasmaw s
1％一5％withregardtobothintra-dayan lysisof
anyconcentrationonthestandardcurveandinter—
daycomparisonof tandardcurves(Table1)．
Tahie1 RelaDrestandarddevlatloasofl trs-dayandlater—
flaypree|sloasformethodt determinegomcentt-8-
tionsofarJstolochlcacidAinplasma抽一5)
Concentration／Coefficientofvariation／％
(pg·mL一。) Intra—day Inter—day
2．6 I。imitofdetection：Theminimaldetectable
concentrationofaristolochica idAwas0．0183
pg／mL(S／N≥3)．
2．7 Medicationandsampling[3_6]：Suitablequan—
titlesofR口d如AristolochicaeandGuanxinsuhe
Capsulew retransferredandextractedwith
methan01bySoxhlet—extractionfor8 h．Theex—
tractsolutionswereconcentratedtodryandthe
residuesw redissolvedin olumetricflasksrespec—
tivelywithmethan01．Analiquotv lumeofthex—
tractwasfilteredthrougha 0．45gmfilterandin—
iectedintoHPLC．Theresultsshowedtheconeen—
trationsfaristoloehicacidAinthextractof
RadixArlstolochicaeandGuanxinsuheCapsule
were0．02857％and0．02876％，respectively．
RadixAristolochicaepowderndthecontents
ofGuanxinsuheCapsuleweresuspendedwith
0．3％CMC—Naasthetestsolutionsf rfuture
use．Theconcentrationsofaristolochica idAin
thesuspensionsofRadixAristolochicaeand
GuanxinsuheCapsulewere95．41pg／mLand
97．42Pg／mL，respectively．
MiceweregivenRadizAristolochicaeor
GuanxinsuheCapsulesuspensionbyigatdoseof
2．5mg／kgofaristolochicacidA．Plasmaconcen—
trationsweredeterminedbyHPLC．Sixm cewere
studiedateachtimepoint．Bloadwascollected
fromarteriesoftheyepitntoheparinizedglass
tubes．Sampleswereobtainedat5，10，15，20，
30，45，60，90，120，150，180，and240minafter
igadministration，respectively．Thebloodsamples
werec ntrifuged(3000×gfor10min)toobtain
plasmaandanalyzedimmediately．Amethanolso—
lution(0．6mL)wasaddedto0．2mLaliquotsof
plasmasample．After10svo texand10rainten—
rifugation3000×g，thesolutionwasfiltrated
withfilter(0．45Ⅱm)andinjectedforHPLC
analysis．
2．8 Pharmacokineticanalysis：Timecoursesof
plasmaconcentrationsofaristolochica idAin
RadixAristolochicaeandGuanxinsuheCapsule
wereanalyzedby3P97softwareusingweighted
least—squaresestimationET]．Theconcentration—time
curvesofaristolochica idAwerefittedtoone—
compartmentmodelaccordingtotheminimum
Akaike’eInformationCr terion(AIC)．themini—
mumsquaresum(SUM)，andthemaximumrela—
tivecoefficient(Fig．2)．
TheConcentration—timecurvesofarist010chic
acidAwerefittedtoone—compartmentmodel．
Eachmousewasgiventhesamedoselevelof
万方数据
中草药ChineseTraditionalandHerbalDrugs第36卷第11期2005年11月
1 6
1 4
1．2
1
d8
06
04
02
0 306090120150180210240
，／Illln
1-RadixAmjtolvchlcaeg-GuanxinsuheCapsule
Fig．2Meanconcentration—timecurv∞ofaristolochlc
acidAinmiceaftcrRadizAristolaeMeae
andGuanxinsuheCapsuleadministration
aristolocbica idAinRadixAristolochicaeorjn
GuanxinsuheCapsule．therewasa significantdi—
fferenceint rmsofthemaximumplasmaconcen—
trationofaristoloehieacidA(C。；)andthearea
undertheconcentration—timecurve(AUC)．The
responsetoGuanxinsuheCapsuledemonstrateda
significantdecreaseinG№andAUC．Therewas
nosignificantdi—ffefencebetweenRadixAHstolo-
chicaendGuanxinsuheCapsuleint rmsofplasma
half—lifeo aristolochica idAandthetimepeak
(k。)ofplasmaaristolochicacidA(Table2)．
Table2 Pharmacokineticparametersofa istolochic
acidAinmiceaftero aladministration
Para耻ters Ufit-----------------------一Aritst0·iot&ic·—-—·-—·----u-u----------一
“诅^
R幽z^珈d∞^“GuaaxirmheCapsule
3 Discussion
Thisstudypresentedth videncethatGuanx—
insuheCapsulewasabletoaffecttheabsorptionof
aristolochica idAfirst．Thepr sentpharma—
cokineticstudyshowsthatpharmacokineticsof
aristoloehieacidAfromRadixAristolochicaeand
GuanxinsuheCapsuleaftero sIadminitrationis
different．Forexample，thevalu sofA，lagtime，
AUC，andC。。forGuanxinsuheCapsulearless
thanthoseforRadixAristolochicae．Thisindicate
thattheamountofaristoloehicacidAinGuanxin—
suheCapsuleabsorbedbymicewasless．Atthe
samecontent1evelofaristolochicacidAadminis—
tered，theabsorptionofaristolochiea idAin
RadixAristolochicaesupplementedwithotherin—
gredientsi GuanxinsuheCapsulewasignificantly
reducedomparedwiththatinRadixAristolochicae
alone．Thus，theresultssuggestthatherenal
toxicityofGuanxinsuheCapsulewouldbelesssig—
nifieantthanhatofRadixAristoloehicaealone．In
thispaper，amethodusedtodeterminetheplasma
concentrationofaristolochica idAinmicewas
successfullyestablishedby RP—HPLC．The
methodhasbettercharacteristicsw thselectivity，
1inearity，andsensitivityandissuitableforthe
evaluationinpharmacokineticstudies．
UPtonow，130articlehasdemonstratedth
GuanxinsuheCapsulecouldcausethearistoloehic
acidnephropathy(AAN)．However，asknown，
aristolocbieacidcancausetheprogressiveintersti—
timfibrosisofthekidneyrapidly．AsGuanxinsuhe
Capsuledo scontainristoloehieacidA，itshould
beusedwithcaution．
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[53ZhansYP，XuGJ，JinRL．eta1．Determinationofaris—
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[63ZhangXM．ZhengFLTheChineseherbnephropathyin
dueedbynristolochlca id[J]．IV删ldNephra$(国外医学‘越
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万方数据
青木香和冠心苏合胶囊中马兜铃酸A的药动学研究
作者： 田葆萍， 张兰桐， 袁志芳， 刘伟娜， 刘红菊， TIAN Bao-ping， ZHANG Lan-tong，
YUAN Zhi-fang， LIU Wei-na， LIU Hong-ju
作者单位： 田葆萍,TIAN Bao-ping(河北医科大学药学院,药物分析教研室,河北,石家庄,050017;总装备
部后勤部军事医学研究所,北京,100101)， 张兰桐,袁志芳,刘伟娜,刘红菊,ZHANG Lan-
tong,YUAN Zhi-fang,LIU Wei-na,LIU Hong-ju(河北医科大学药学院,药物分析教研室,河北
,石家庄,050017)
刊名： 中草药
英文刊名： CHINESE TRADITIONAL AND HERBAL DRUGS
年，卷(期)： 2005,36(11)
被引用次数： 1次
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