1、ms |:R965.3 DS M :A cI|:1002-3127(2006)04-0262-03 8 s80 Z王庆利,彭健(国家食品药品监督管理局药品审评中心,北京 100038)1oM:s80;Q0;0;L.; 3;Te: i ,0 p V,Z_:0 r N。s80 (Tween 80, polyoxyethylene 80 sorbitanmonooleate, ?80), Bd 0V 4, VT 4、s 4、9 44,i0, ,y7 s80T A。 sY r H A、1cY?s80 A, r H4 M, 4sYs80 100 mg kg、Y?5 mg/kg、s80 10 mg kg。
2、T Vn,s80F ( 60%,7Y?Fn,4 U1 4s80 6 。1.2 单次给药毒性研究 “ -XQ0 k。(1)v Q s80 456 mg kg,n,nF 6;(2)EtQs80 200、500800 mg/kg,200 mg/kgFn AY。500 mg kgFC5 = 、 %hl,03 h= b%?( x) 6,6 12 hr,24 48 h 。800 mg kgF5C 7 ;(3) s80 4,C “5,Q s8040 qM1。s80 46 15 mg kg, 34 min, VnQ,VCr、 g0()?, 9 n, AP-, V ?F 61。 q0 H(25 100 mg k
3、g,1.5 2 h),C FQ。cs80 (8 mg/kg) 4QG(40 mg/m2 ,30 min ),CBV( l 、 f、 ( A) Q( )8 。G4 A “5r4 ,# Q 4s80 。VD s80 4 (50%lethal dose,LD50)Kl 4 (minimum lethaldose,MLD)nV19-10 。V T Vn,s80B S, s80 Es 。V1 s80 LD50MLD 0oLD50(g/kg) MLD(g/kg)l 5.8l 8 8.1v 1.79 1v 8 6.8 10 0.5 0.51.3 重复给药毒性研究1.3.1 经口给药毒性11 :l v , k
4、gc0、3 、6、12.5、2550 gs80 , 14 d, LVn ,K4 Fv (89 AvF。ns80M1 “5M、 # M# M。 4 013,n ,0Fl v (8M vFM 。ns80M1 “5M、 # M# M、v262 2006 M820 4 J Toxicol August 2006 Vol.20 No.4DOI :10.16421/ki .1002-3127.2006.04.02384A4 。 T4 U, s80c r5% H,n A。1.3.2 消化道外途径给药:(1)Fischer 344v s80(20 min),4 100 175 mg (kgd)(8V w ,M
5、60 kg ,/)972 1 701 mg/d), 1, Vn _ %9 6;(2) 30ZsYs8012 :1F, = 40 mg/kg (M 1 298 mg,3/5I),1Q/, 06;2F, =5 mg/kg(M 162 mg,1/2I),1Q/3 d , 3Q;3F, 52 mg (kgh)(M 1 688 mg/h ,1/1I), 3?。1F C n, k , ,$; 、 、 ;(3) J (20 min)s804 75 mg (kgd)(M 1 458 mg/d), 30,ns。 T4 U,s80 gho0 3M z。1.4 遗传毒性研究11 (S9) H,s80 e )TA10
6、0、TA1535、TA1537TA98nlMT。1.5 生殖与发育毒性研究 (CDv 1 (0 19 d s804 12.5、5075 mg/kg,0 HW1 1.5 min,4 F (n 8?。 ( t1 (7 19? s804 37.5、5062.5 mg kg(5 ml/kg, 50 ml/h),187.5 mg kg (10 ml/kg,100 ml/h)。187.5 mg/kgFC A 8(8, J h ) -(8)。 3Iv ,1 34 7? 8 s804 1、510 mg/kg,5 - H 4?Cs80 V ,? f ,? f , x8,C|M x 。0vF1 ,00 xM h
7、。0 $ % 3,0%M4 UI “O 13 。 Williams14?C,Iv 320 22 d gs80,4 r5 g (kgd),n0 Y。1.6 致癌性研究 11 B6C3F1l F344/Nv , FI60, kgc0(vF)、2550 gs80 , 103。015 ,4 FIl C -9 3? 3 q9F,n M1s。 L Vn4 FIl (8vF11%,ns80M1 “5VC。0Fv i qvF(vF29 50,4 F18/50,4F18/50), Fi qvFM(Iv:23/50, 25/50, 25/50;l :33/49, 34/50,32/50;Il :30/50,28/
8、50,26/50)。v / F _% ? 3 q 6(21/50,19/50,29/50)。4 Fv / F 9 3? 3 q9F,4 Fn 6(11/50,22/50,12/50)。Il ns80M1 ? 3 q9F。4 FIl - $ 9 3? 3 q A9F,4 FIl - ? 3 qA9F。 ,N LHq/,v n / F _% ? 3 q9F,yN,s80vil ,7Il v n。2 “5 “51 r H5“dY,4 U510 mg kgr HCBVV (0 -4 min), 4s80(1020 mg/kg) 15-16 ,s809P i l 1。1 cs80 !C (- ) 17
9、。3 Zs80Xv godho04, 。TA Us80 z 3, (Et cs80 187.5 mg/kg V A 8, -8BY,4 l263 2006 M820 4 J ToxicolAugust2006 Vol.20 No.462.5 mg/kg HnY。Q0 H,4 80()、56(v )188(Et)mg/kg H,n A。 s80 Es , V 3 AFQ,yN V ? acs804 ,+Y 4。 ?Cs80 30 , F ?18 。s80|Bt 4 0 , ,L ?YV 7 p Bt 7 ?19 。 V ?/ 7 =s80 9F7,Gelperina20?C,s80 , 0 V
10、?9F。8 9F T1B,“s m / 21 ,s80 8S e|F 。 ID: 1 Daher CF, BaroodyGM, Howland RJ.Effect of a surfactant,Tween 80, on the formation and secretion of chylomicrons inthe rat.Food Chem Toxicol, 2003,41:575-582. 2 Masini E, Planchenault J, Pezziardi F, et al.Histamine-releasing properties of Polysorbate 80 in
11、vitro and in vivo:correlation with its hypotensive action in the dog.AgentsActions, 1985, 16:470-477. 3 Krantz JC, Carr CJ.Sugar alcoholsXXVII;drug allergy in thecanine family.J Pharmacol Exp Ther, 1949, 97:125-128. 4 Krantz JC, Carr CJ, Bird JG, et al.Sugar alcoholsXXVI;Pharmacodynamic Studies of P
12、olyoxyalkylene Derivatives ofHexitol Anhydride Partial Fatty Acid Esters.J Pharmacol ExpTher, 1948, 93:188-195. 5 Eschalier A, Lavarenne J, Burtin C, et al.Study of histaminerelease induced by acute administration of antitumor agents indogs.Cancer Chem Pharmacol, 1988,21:246-250. 6 Gough WB, Zeiler
13、RH, Barreca P, et al.Hypotensive actionof commercial intravenous amiodarone and polysorbate 80 indogs.J Cardiovasc Pharmacol, 1982,4:375-380. 7 Kellner A, Correll JW, Ladd AT.Sustained hyperlipemiainduced in rabbits by means of intravenously injected surface-active agents.J Exp Med, 1951, 93:373-384
14、. 8 OgilvieGK, Cockburn CA, Tranquilli WJ, et al.HypotensionanPMID-2972235; Hypotension and cutaneous reactionsassociated with intravenous administration of etoposide in thedog.Am J Vet Res, 1988,49:1367-1370. 9 Krantz JC, Culver PJ, Carr CJ, et al.Sugar alcoholsXXVIII;Toxicologic, Pharmacodynamic a
15、nd clinical observations onTween 80.Bull SchoolMed, U of Maryland, 1951,36:48-56. 10 Varma RK, Kaushal R, JunnarkarAY, et al.Polysorbate 80:a pharmacological study.Arzneimittelforschung, 1985,35:804-808. 11 NTP.Toxicology and Carcinogenesis Studies of Polysorbate 80(CAS No.9005-65-6) in F344 N Rats
16、and B6C3F1 Mice(Feed Studies).Natl Toxicol Program Tech Rep Ser, 1992,415:1-225. 12 AulettaCS, Reynolds DL, Kelly CM, et al.Adverse effects ofTween 80 in dogs.Fundam Appl Toxicol, 1996,30:101. 13 Gajdova M, Jakubovsky J, ValkyJ.Delayed effectsof neonatalexposure to Tween 80 on female reproductive or
17、gans in rats.Food Chem Toxicol, 1993,31:183-190. 14 Williams J, Odum J, Lewis RW, et al.Theoral administrationof polysorbate 80 to the immature female rat does not increaseuterine weight.Toxicol Lett, 1997, 91:19-24. 15 Munoz A, Karila P, Gallay P, et al.A randomizedhemodynamic comparison of intrave
18、nous amiodarone with andwithout Tween 80.Eur Heart J, 1988,9:142-148. 16 SicartM, BesseP, Choussat A, et al.Hemodynamic effects ofintravenous amiodarone in humans.Arch Mal Coeur Vaiss,1977,70:219-227. 17 Levy M, Dupuis LL.Parenteral nutrition hypersensitivity.JParenter Enteral Nutr, 1990,14:213-215.
19、 18 TenTije AJ, Verweij J, Loos WJ, et al.Pharmacologicaleffects of formulation vehicles: implications for cancerchemotherapy.Clin Pharmacokinet, 2003, 42:665-685. 19 Sun W, XieC, Wang H, et al.Specific role of polysorbate80coating on the targeting of nanoparticles to the brain;Specificroleof polyso
20、rbate 80 coating on the targeting of nanoparticlestothe brain.Biomaterials, 2004, 25:3065-3071. 20 GelperinaSE, Khalansky AS, Skidan IN, et al.Toxicologicalstudies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate)nanoparticles in healthyrats and ratswithintracranial glioblastom
21、a.Toxicol Lett, 2002,126:131-141. 21 Baker SD, Zhao M, He P, et al.Simultaneous analysis ofdocetaxel and the formulation vehicle polysorbate 80 in humanplasma by liquid chromatography tandem mass spectrometry.And Biochem,2004,324:276-284.( l :2005-08-28)264 2006 M820 4 J Toxicol August 2006 Vol.20 No.4
