硫酸多粘菌素E注射液及其药物动力学研究

E100094EpHE2.5%E5.0%EELD5038.72mgkg-1431.39mgkg-110.0mgkg-115d2.5%E15.0mgkg-115d4～5d10.0mgkg-15d2.55.0mgkg-1Cmax3.73±0.286.40±0.18µgml-132±1.534±1.8mint1/2β256±14264±29min2.5mgkg-1t1/2β251±13min2.55.0mgkg-198.30%88.54%E2.5mgkg-1BW2EStudiesontheInjectabIeSoIutionofCoIistinSuIfateandItsPharmacokineticsXIAOXi-longLINBinZHANGChun-pingCollegeofVeterinaryMedicineChinaAgriculturalUniversityBeiji[e-mail]colistinsulfatecontainscolistinsulfatelocalanaesthesiaantioxygenandotheradditaments.Theexperimentalresultsshowedthatthenovelpreparationwasstableeitherinheatorinlight.Thetermofvalidityofthepreparationwas2yearsatroomtemperature.Thepreparationcontaining25.0mgml-1ofcolistinsulfateshowednolocaltissueirritationbuttheconcentrationof50.0mgml-1showedobviouslocaltissueirritation.ResultofacutetoxicitytestshowedthattheLD50ofintramuscularinjectioninmicewas38.72mgkg-1andoralLD50was431.39mgkg-1.Theevidenceofneurotoxicitywasobservedinmiceintheacutetoxicitytest.Adoseof10.0mgkg-1or15.0mgkg-1BWwasadminidteredintramuscularlytopigletoncedailyfor5days.Nochangesweredetectedinthepigletbodyexceptfortheslightepithelialtissuesgranulardegenerationsinthekidneyandliveratthedoserateof10.0mgkg-1.Atthedoserateof15.0mgkg-1theobviousneurotoxicitywasobservedat4-5days.Theepithelialtissuesinthekidneyandlivershowedmoderategranulardegenerationsespecialtubulirenalescells.Theresultofbloodcellsmorphosisindexesshowednormal.Withrelationtoliversfunctiontheindexeswentbeyondthenormalscope.Otherwisewithrelationtokidneysfunctiontheindexesshowedmostlynormal.Injectionwasseparatelyadministeredintomus-cleIMinpigswiththedosesof2.5and5.0mgkg-1BWwhoseCmaxwere3.73±0.28and6.40±0.18µgml-1Tmaxwere32±1.5and34±1.8mint1/2βwere256±14and264±29mininjectionwasadministered2003363329-335ScientiaAgriculturaSinicaintoauralveinIVwiththedoseof2.5mgkg-1BWwhoset1/2βwas251±13min.Examplesoftheexperi-mentallydeterminedserumconcentrationofcolistinsulfategeneratedtwo-exponentialmodelwithfirst-orderab-sorption.Themeanabsolutelybioavailabilitycoefficientof2.5and5.0mgkg-1BWIMwere98.30%and88.54%.Thehighbioavailabilityandthelongmaintainingtimeofthevalidblood-drugconcentrationshowthattheinjectionisgoodforIMinpigstherecommendeddoseis2.5mgkg-1BWtwicedaily.KeywordsColistinsulfatePharmacokineticsEcolistinsulfateβ-EEEvans1EE11.1E694µgmg-1E643.5µgmg-1CMCCB441031.2EE2.5%5.0%EECMCCB44103E1.3E2.5%5.0%2E1.4E1.4.1LD50300360432518622mgkg-1BWE25303643.251.84mgkg-1BWELD50LD501.4.2510～15kg210.0mgkg-1BW2.5%E15d315.0mgkg-1BW2.5%E15d012345710101.4.31.5kg624h2.5%5.0%E0.5ml48h22.5%5.0%E0.5ml48h1.4.4E11020333652.5mgkg-1BW5.0mgkg-1BW2.5mgkg-1BW7d21153045601201802403604807201440min5ml337℃2h3000r/min10min-20℃4E1.6µgml-1EE6.4µgml-1122.1E2.1.12.5%5.0%E1E12pHTable1Theresultsoftemperature-humiditystabilitytestof2.5%and5.0%colistinsulfatesolutionsrelativeconcentrationchangeofpHTimemonth2.5%%ConcentrationpH2.5%%ConcentrationpH5.0%%ConcentrationpH5.0%%ConcentrationpH01000100.00100.00100.00198.66+0.1099.55+0.2299.56+0.0599.100297.56097.56+0.1297.78+0.0597.80-0.02396.90+0.2196.46+0.0796.25-0.0396.03-0.05496.03+0.1795.17+0.0294.53-0.0594.74-0.10593.47+0.1294.11+0.0592.01-0.1091.39-0.05690.58+0.0292.22+0.0289.76-0.1588.16-0.252.1.296.9%～98.88%pH-0.08～0.362.5%5.0%E22.1.32.5%5.0%2E2EE2ETable2Thechangeofdifferentconcentrationinjectablesolutionofcolistinsulfate55℃dTimemgml-1Concentration65℃dTimemgml-1Concentration75℃dTimemgml-1Concentration85℃dTimemgml-1Concentration2.5%024.833024.833024.833024.833424.500224.611124.5000.524.555824.226424.117224.2811.024.2261224.063624.009323.9551.523.7941623.955823.687423.6872.023.6345.0%050.454050.454050.454050.454450.115249.890149.5540.549.443849.332449.443248.8901.048.6701248.890648.890348.1261.547.9101648.018848.561447.3742.047.2681333E22.5%5.0%288.0177.71kJmol-125℃EK1.3074×10-41.3596×10-4t0.9=0.1054/Kt0.5=0.693/K2t0.92.212.12t0.514.52213.962.1.42EpH0.03～0.1097.56%～98.66%E2.1.52.5%5.0%E96.68%～98.0%pH0.04～0.12E2.2E2.2.1LD50EELD5038.72mgkg-1431.39mgkg-195%35.72～41.97mgkg-1414.32～449.16mgkg-12.2.210.0mgkg-1215.0mgkg-13452h24～48h15.0mgkg-11210.0mgkg-115.0mgkg-1TPALBGLU45710.4710.209.67mmolL-112.8～387.7µmolL-110.0mgkg-12274.7µmolL-1ALTASTALPγ-GGTLD10.0mgkg-1ALTASTALPGGTLD4112315.0mgkg-11222710210.0mgkg-115.0mgkg-12.2.3648h2.5%E5.0%E2.3E2.3.1E32.3.233P97X±SD44E5.0mgkg-1BWC=8.4444e-0.01417t+2.7122e-0.00265t-11.1566e-0.06491t233363E1µgml-1Table3PlasmaconcentrationofcolistinsulfateinpigletMean±SDn=5TimeminIntramuscular5mgkg-12.5mgkg-1Intravenous2.5mgkg-10155.31±0.292.97±0.163.15±0.13306.33±0.263.74±0.272.82±0.09456.16±0.163.59±0.272.45±0.18605.65±0.163.19±0.282.17±0.121203.53±0.201.93±0.111.59±0.131802.38±0.191.25±0.081.28±0.102401.69±0.130.90±0.071.06±0.123601.07±0.120.61±0.040.81±0.064800.79±0.110.40±0.030.52±0.077200.41±0.080.22±0.020.28±0.0314401Notdetectable4ETable4PharmacokineticparametersofcolistinsulfateinpigletMean±SDn=5VariableUnitIntramuscular5mgkg-12.5mgkg-1Intravenous2.5mgkg-1Aµgml18.44±0.865.23±0.681.69±0.