1 : 155,,, [10], P450 (Carassius auratus gibelio),,, ( 98%) ( ) ; (Enrofloxacin, ENR) (Cipmfloxacin, CIP) 99.5%, Sigma ; ( 98.0%) 7- Sigma, Ⅱ (N

Size: px

Start display at page:

Download "1 : 155,,, [10], P450 (Carassius auratus gibelio),,, ( 98%) ( ) ; (Enrofloxacin, ENR) (Cipmfloxacin, CIP) 99.5%, Sigma ; ( 98.0%) 7- Sigma, Ⅱ (N"

党蠡强
5 years ago
Views:

1 2012 1, 19(1): Journal of Fishery Sciences of China 研究论文 DOI: /SP.J 房文红 1, 周常 1,2, 孙贝贝 1, 李国烈 1, 杨先乐 2, 李新苍 1 1, 胡琳琳 1., ; 2., 摘要 : (baicalin, BL) (glycyrrhizin, GZ) (Carassius auratus gibelio), (enrofloxacin, ENR) CYP1A CYP3A 7 d (100 mg/kg) (100 mg/kg), 24 h 10 (10 mg/kg),, HPLC (cipmfloxacin, CIP), ; 6 CYP1A CYP3A : (1) (BL) (GZ) (C max ), (AUC) ; (2) BL GZ, (t 1/2z ) (P<0.05), (CLz/F), ; (3) BL GZ, BL GZ C max-cip /C max-enr 1.48% 2.22%, 0.95%; BL GZ AUC 0-t-CIP /AUC 0-t-ENR 2.16% 1.76%, 1.7% C max-cip /C max-enr AUC 0-t-CIP /AUC 0-t-ENR, N- ; (4), BL GZ 7- -O- (EROD, CYP1A ) -N- (ERND, CYP3A ) (P<0.05), CYP1A CYP3A CIP, CYP1A CYP3A : ; ; ; ; ; CYP450 中图分类号 : S94 文献标志码 : A 文章编号 : (2012) ,, [1], (drugdrug interactions, DDIs) DDIs,, DDIs 40% [2], DDIs P450 (CYP450),, CYP450 [3], CYP1A2 [4] ; CYP3A4, [5] (baicalin, BL) (glycyrrhizin, GZ), [6] [7],,, [8] ;, C max (AUC), [9], 收稿日期 : ; 修订日期 : 基金项目 : ( ); ( )(2007M06). 作者简介 :,,.Tel: whfang06@yahoo.com.cn

2 1 : 155,,, [10], P450 (Carassius auratus gibelio),,, ( 98%) ( ) ; (Enrofloxacin, ENR) (Cipmfloxacin, CIP) 99.5%, Sigma ; ( 98.0%) 7- Sigma, Ⅱ (NADPH) (HPLC ), ( ) 1.2, Waters 2695, Zorbax SB-C 18 (5 µm, mm, I.D.), Waters 2475 (Beckman Optima L-100XP), (, 970CRT), (, UV-2802S), ( 80, Thermo), (, Millipore Advantage A10), (, Mettler Toledoab 204, g), (, HITACHI CF16RXⅡ), 0.22 μm 1.3, (200±13) g, 5 35 cm 80 cm 45 cm,, 26~27,, 4 100% 1.4, 0.1 mol/l, 10 mg/ml 3, 20, (BL ) (GZ ), 100 mg/(kg d), 7 d, 1, 5 min 24 h, 6 ;, BL GZ 10, 10 mg/kg, 20 cm 40 cm 30 cm, 5 min 30 min 1 h 2 h 4 h 8 h 12 h 1 d 2 d 3 d 4 d 0.3 ml, 1.5mL, r/min 10 min, ,, 200 μl 1.5 ml,, 2 min, r/min 5 min, 0.22 μm, HPLC 1.6 : 0.01 mol/l ( ph=2.8)=5:95(v/v), 10 min; 40 ; 1.2 ml/min; 10 µl; E x =280 nm, E m =450 nm 1.7 Novi [11] ; 7- -O- (EROD) Lange [12] ; -N- (ERND) Tu [13]

3 , DAS ENR 1 BL ENR, (T max ) (C max ) 0.5 h (7.685±2.392) mg/l; GZ ENR 1, T max =0.083 h, ENR (C max ) (5.769±1.164) mg/l (10.470± 2.088) mg/l BL GZ ENR C max 76% 55% 1 - Fig.1 Mean plasma ENR concentration vs. time curves of crucian carp after coadministration of BL and GZ 2.2 ENR, 1 BL GZ (AUC 0-t ) mg h/l mg h/l, 46.40% 47.81% BL, (t 1/2z ) h, GZ, h, (37.38 h); BL GZ (CL z/f ), CIP 2 3 CIP,, GZ T max, 8 h, C max, (0.099± 0.029) mg/l (0.128±0.024) mg/l; BL, T max =12 h, C max (0.114±0.028) mg/l BL GZ C max-cip /C max-enr 1.48% 2.22%, 0.95% 2.4 CIP, ENR CIP, 2 BL GZ (MRT) (V z/f ) t 1/2z, (CL z/f ) BL GZ CIP (AUC), BL GZ AUC 0-t-CIP /AUC 0-t-ENR 2.16% 1.76%, 1.7% 2.5 P450 BL GZ, CYP1A CYP3A 3 BL EROD ERND (P<0.05), GZ EROD ERND (P<0.01),, P450, P450,, 7 d CYP1A [14], 14 d CYP3A [15], LS174T CYP3A4 [16] [17] (Paralichthys olivaceus) CYP1A, CYP1A,, EROD ERND CYP1A CYP3A,

4 1 : 157 Tab.1 表 1 腹腔注射给药后恩诺沙星在异育银鲫血浆中药动学参数 ( 统计矩原理 ) Pharmacokinetic parameters of enrofloxacin in plasma from crucian carp after intraperitoneal injection based on statistical moment theory n=10 pharmacokinetic parameter control baicalin glycyrrhizin C max /(mg L 1 ) ± ± ±1.164 T max /h AUC 0-t /(mg h L 1 ) AUC 0- /(mg h L 1 ) MRT 0-t /h MRT 0- /h V z/f /(L kg 1 ) t 1/2z /h CL z/f /(L h 1 kg 1 ) : C max ; T max ; AUC 0-t AUC 0-0-t 0- ; MRT 0-t MRT 0-0-t 0- ; V z/f ; t 1/2z ; CL z/f. Note: C max -peak OTC concentration; T max -time to reach peak concentration; AUC 0-t -area under the concentration-time curve from zero to time t; AUC 0- -area under the concentration-time curve from zero to infinity; MRT 0-t area residence time from zero to time t; MRT 0- area residence time from zero to infinity;v z/f -the apparent volume of distribution; t 1/2z -elimination half-life; CL z/f -total body clearance. 2 - Fig.2 Mean plasma CIP concentration vs. time curves of crucian carp after coadministration of BL and GZ 7 d,, P450 [18],,, [19], C max, BL GZ C max-cip /C max-enr 1.48% 2.22%, 0.95%; BL GZ AUC 0-t-CIP / AUC 0-t-ENR 2.16% 1.76%, 1.7% C max C max-cip /C max-enr AUC 0-t-CIP /AUC 0-t-ENR, N- Vaccaro [19] (Dicentrarchus labrax) P450, NADPH, P450, N-, CYP1A CYP3A, X (PXR), CYP3A, CYP3A N- [15], CYP1A P450 N-,, CYP [20],, CYP1A CYP3A N-,

5 Tab.2 表 2 腹腔注射给药后代谢产物环丙沙星在异育银鲫血浆中药动学参数 ( 统计矩原理 ) Pharmacokinetic parameters of ciprofloxacin in plasma from crucian carp after intraperitoneal injection based on statistical moment theory n=10 pharmacokinetic parameter control baicalin glycyrrhizin C max /(mg L 1 ) 0.099± ± ±0.024 T max /h AUC 0-t /(mg h L 1 ) AUC 0- /(mg h L 1 ) MRT 0-t /h MRT 0- /h V z/f /(L kg 1 ) t 1/2z /h CL z/f /(L h 1 kg 1 ) : C max ; T max ; AUC 0-t AUC 0-0-t 0- ; MRT 0-t MRT 0-0-t 0- ; V z/f ; t 1/2z ; CL z/f. Note: C max peak OTC concentration; T max time to reach peak concentration; AUC 0-t area under the concentration-time curve from zero to time t; AUC 0- area under the concentration-time curve from zero to infinity; MRT 0-t area residence time from zero to time t; MRT 0- area residence time from zero to infinity; V z/f apparent volume of distribution; t 1/2z elimination half-life; CL z/f total body clearance. Tab. 3 表 3 BL 和 GZ 对异育银鲫肝 CYP1A 和 CYP3A 活性的影响 Effects of BL and GZ on CYP1A and CYP3A activities of liver from crucian carp 1 n=6; x ±SD; pmol min 1 mg dose/ EROD ERND group (mg kg 1 d 1 ) EROD activity ERND activity baicalin ±2.64 * ± ** glycyrrhizin ±3.99 * ±98.96 ** control ± ± : * (P<0.05), ** (P<0.01). Note: *donates singnificant difference with control (P<0.05). **donates extremely singnificant difference with control (P<0.01). C max AUC 0-t (t 1/2z ) (CL z/f ),,,, CYP1A2, [4] ;, [8] ; A t 1/2,, AUC, [21] ;, A AUC C max A t 1/2, [22], P450 ( CYP3A), P- P-, ATP (ABC),, [23] Bauer [24] (Hypericum perforatum) P- A [25] [26] P-, [25 26] P-,,

6 1 : 159 (pefloxacin) [27], (danofloxacin) [28] ; Seelig [29] P-,, P- P-, P-, ENR 73, 27, [30],,,, 参考文献 : [1]. [J]., 2003,1(4): [2],,. - [J]. :, 2009, 28(2): [3],,. P450 [J]., 2011, 38(1): [4] Kubota Y, Kobayashi K, Tanaka N, et al. Pretretment with Ginkgo biloba extract weakens the hypnosis action of Phenobarbital and its plasma concentration in rats [J]. Pharmacology, 2004, 56(3): [5] Harkey M R, Henderson G L, Gershwin M E, et al. Variability in commercial ginseng products: An analysis of 25 preparations [J]. Am J Clin Nutr, 2001, 73: [6] Isbrucker R A, Burdock G A. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin [J]. Regul- Toxicol Pharmacol, 2006, 46: [7] Chang H H, Yi P L, Cheng C H, et al. Biphasic effects of baicalin, an active constituent of Scutellaria baicalensis Georgi, in the spontaneous sleep-wake regulation [J]. J Ethnopharmacol, 2011, 135(2): [8] Velpandian T, Jasuja R, Bhardwaj R K, et al. Piperine in food: interference in the pharmacokinetics of phenytoin [J]. Eur J Drug M etab Pharmacokinet, 2001, 26(4): [9],,,. LC-MS/MS [J]., 2010, 30(9): [10]. [M]., 2008: 53,173. [11] Novi S, Pretti C, Cognetti A M, et al. Biotransformation enzymes and their induction by β-naphtoflavone in adult sea bass (Dicentrarchus labrax) [J]. Aquat Toxicol, 1998, 41: [12] Lange U, Goksøyr A, Siebers D, et al. Cytochrome P450 1A-dependent enzyme activities in the liver of dab (Limanda limanda): kinetics, seasonal changes and detection limits [J]. Comp Biochem Physiol, 1999, 123B: [13] Tu Y Y, Yang C S. High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting [J]. Cancer Res, 1983, 43: [14],,,. P4501A2 [J]., 2007, 7(4): [15]. CYP450 [D]. :, [16] Li Y, Wang Q, Yao X M, et al. Induction of CYP3A4 and MDR1 gene expression by baicalin, baicalein, chlorogenic acid, and ginsenoside Rf through constitutive androstane receptor-and pregnane X receptor-mediated pathways [J]. Eur J Pharmacol, 2010, 640: [17],,,. CYP1A [J]., 2010, 17(5): [18],,,. P450 [J]., 2011, 27(4): [19] Vaccaro E, Giorgi M, Longo V, et al. Inhibition of cytochrome P450 enzymes by enrofloxacin in the sea bass (Dicentrarchus labrax) [J]. Aquat Toxicol, 2003, 62: [20] Yoo H H, Kim N S, Lee J, et al. Characterization of human cytochrome P450 enzymes involved in the biotransformation of eperisone [J]. Xenobiotica, 2009, 39: [21],,,. [J]., 2002, 16(1): [22],,,. A [J]., 2006, 41( 9): [23] Schinkel A H, Jonker J W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview [J]. Adv Drug Deliv Rev, 2003,55(1): 3 29.

7 [24] Bauer S, Stormer E, Johne A, et al. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John s wort in renal transplant patients[j]. Br J Clin Pharmacol, 2003, 55: [25]. CYP450 [D]. :, [26]. 18 P- [D].. :, [27] Seelig A, Landwojtowicz E. Structure activity relationship of P-glycoprotein substrates and modifiers [J]. Eur J Pharmacol Sci, 2000, 12: [28] Schrickx J A, Gremmels J F. Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters [J]. Br J Pharmacol, 2007, 150(4): [29] Seelig A, Landwojtowicz E. Structure activity relationship of P-glycoprotein substrates and modifiers [J]. Eur J Pharmaceutical Sci, 2000, 12: [30]. [M]. :, Effect of baicalin and glycyrrhizin on enrofloxacin in vivo in crucian carp (Carassius auratus gibelio) FANG Wenhong 1, ZHOU Chang 1.2, SUN Beibei 1, LI Guolie 1, YANG Xianle 2, LI Xincang 1, HU Linlin 1 1. East China Sea Fisheries Research Institute, Chinese Academy of Fishery sciences; Key Laboratory of Marine and Estuarine Fisheries Resources and Ecology, Ministry of Agriculture, Shanghai China; 2. National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai , China Abstract: Cytochrome P450s (CYPs) widely distribute in the liver of aquatic organisms and play a key role in drug metabolism. CYPs catalyze the N-deethylation of Enrofloxacin (ENR) to Ciprofloxacin (CIP). However, there is limited information regarding the action of CYPs in fish. We evaluated the metabolism of ENR following oral administrated of baicalin (100 mg/kg) and glycyrrhizin (100 mg/kg) in crucian carp, Carassium auratus gibelio. We measured the enzymatic activity of cytochrome P450 1A (CYP1A) and 3A (CYP3A) in liver microsomes. In addition, we documented the pharmacokinetics of ENR by continuous blood sampling. The absorption of ENR decreased significantly over time and both C max and AUC also deceased. AUC and t 1/2z decreased signficantly whereas CL inceased after oral administrated of baicalin and glycyrrhizin, suggesting that ENR elimination was accelerated. The C max CIP /C max ENR was 1.48% and 2.22% for the BL and GZ groups, respectively (control: 0.95%). The AUC 0-t-CIP /AUC 0-t-ENR was 2.16% and 1.76% for the BL and GZ groups, respectively (control: 1.7%). Thus, BL and GZ contributed to induce N-deethylation of ENR. Pretreatment with BL and GZ was associated with a significant (P<0.05) incease in ethoxyresorufin-o-deethylation (EROD) and erythromycin-n-demethylation (ERND) activity, the specific probes for CYP1A and CYP3A, respectively. In summary, BL and GZ accelerated the elimination of ENR. Furthermore, production of the ENR metabolite was related to the induction of CYP1A and CYP3A enzymatic activity. Key words: Carassium auratus gibelio; enrofloxacin; pharmacokinetics; baicalin; glycyrrhizin; CYP450 Corresponding author: FANG Wenhong. Tel: ; whfang06@yahoo.com.cn

< F63756D656E D2D796E2D31C6DABFAF2D31D6D0D2BDD2A9CFD6B4FABBAF2D C4EA2DB5DA34C6DA2DC4BFC2BC2D34C6DA2E6D6469>

< F63756D656E D2D796E2D31C6DABFAF2D31D6D0D2BDD2A9CFD6B4FABBAF2D C4EA2DB5DA34C6DA2DC4BFC2BC2D34C6DA2E6D6469> 梽 / 8 min min doi:.8/wst... R8. [ ] [ ] [] [6] [7] [8] [9~] [ ] [] min t /. min [] 元元元 --9 --7 ZX9-- BLP. ICR ~8 g SCXK -. nanas comosus L. Bolo Leaf Phenols BLP p - coumaric cid.% 巿