Pharmacokinetics and the Elimination Regularity of Difloxacin and its Metabolite Sarafloxacin in Eriocheir sinensis

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1 Chinese Journal of Zoology 2009,44 (2) : ( ) :,, ( Eriocheir sinensis) 20 mgπkg, 2,, V d LΠkg LΠkg LΠkg LΠkg LΠkg ;, t 1Π h h h h h ; CL s LΠh kg LΠh kg LΠh kg LΠh kg LΠh kg, 4 4,,(100 gπkg), 30 gπkg,24 d, : ; ; ; :S941 :A : (2009) Pharmacokinetics and the Elimination Regularity of Difloxacin and its Metabolite Sarafloxacin in Eriocheir sinensis LI Hai2Di YANG Xian2Le 3 HU Kun WANG Xiang2Ling ( Aquatic Pathogen Collection Center of Ministry of Agriculture, Shanghai Ocean University, Shanghai , China) Abstract :The pharmacokinetics of difloxacin (DIF) and its metabolite sarafloxacin ( SAR) in hemolymph, muscle, hepatopancreas, spermary and ovary of Chinese Mitten2handed Crab ( Eriocheir sinensis) were studied by RP2HPLC, after administration by single oral garage of 20 mgπkg. The concentrations versus time in hemolymph, muscle, hepatopancreas, spermary and ovary of E. sinensis were well described by a two2department open model. The results of present studies showed that DIF was rapidly absorbed and extensively distributed in E. sinensis. The apparent volume of distribution (V d ) of DIF of hemolymph, muscle, hepatopancreas, spermary and ovary was LΠkg, (No. 2006BAD03B04) ; 3, E2mail : edu. cn ;,, ; : ; E2mail : heidi - cn : , :

2 2 : LΠkg,11045 LΠkg,11051 LΠkg and LΠkg respectively. DIF eliminated slowly. The elimination half2time (t 1Π2 ) was h, h, h, h and h, respectively, and the total body clearance (CL s ) was LΠh kg, 0104 LΠh kg, LΠh kg, LΠh kg and LΠh kg. The metabolite SAR concentration2time profiles of the hemolymph, muscle, hepatopancreas, spermary and ovary presented similar trend. The multipeak phenomenon were observed, but the peak time of the metabolite SAR in hemolymph, muscle, hepatopancreas, spermary and ovary was the time that the eliminating rate of DIF was very low. Considering that the eliminating rate of DIF and metabolite SAR were very low. Withdrawal time was more 24 d when the maximum residue of DIF is 100 gπkg and of SAR is 30 gπkg after single oral administration of DIF in E. sinensis. Key words : Eriocheir sinensis ; Difloxacin ; Sarafloxacin ; Pharmacokinetics ( difloxacin,dif),, 1984 Abbott [1 ],, [2 ],,,, [3 5 ] [3 ] [4 8 ] [9 ],(25 015),( Eriocheir sinensis),, 1 111, 150,( ) g( ),24 h, 112 ( 9919 %) (sarafloxacin,sar) ( 9916 %),Sigma ; (9913 %,: ), HPLC ;, 113 Agilent21100, DAD 114 : ZORBAX SB2C 18 (150 mm 416 mm,5 m) ; molπl ( ph 311) = 5 95 (vπv) ; 276 nm ; 115 mlπmin ;40 ; 10 l,91365 min, min mgπml,20 mgπkg min, h 015 h 1 h 3 h 6 h 9 h 12 h 24 h 48 h 72 h 96 h 144 h 192 h 240 h 360 h 480 h 528 h 576 h 600 h 8,015 ml ACD 115 ml, , 1 ml ( = ) 5 ml, 2

3 14 Chinese Journal of Zoology 44 min, rπmin 10 min,,45, 1 ml, 0145 m,4 HPLC g,, 1 molπl NaCl 012 molπl PBS (ph 714) 1 ml,5 ml, 10 min, rπmin 10 min, ; 5 ml,,, m,4 HPLC 117 Excel, DAS ,,,, min min( 1), 1 ml, 5 ml Fig. 1 HPLC chromatogram of DIF and SAR in the tissues of in E. sinensis A. (5 gπml) ;B. 3 h ;C. 6 h ;D. 015 h ; E. 3 h ;F. 9 h a, b A. HPLC chromatogram from the standard sample of DIF and SAR ; B. Chromatogram from the hemolymph of E. sinensis at 3 h ; C. Chromatogram from the muscle of E. sinensis at 6 h ; D. Chromatogram from the hepatopancreas of E. sinensis at 015 h ; E. Chromatogram from the spermary of E. sinensis at 3 h ; F. Chromatogram from the ovary of E. sinensis at 9 h. Peak a means DIF, peak b means SAR.

4 2 : 15, ( ) % ( ) %; 417 %, 518 %, 213, h,,015 h (C max = gπml),,6 h (C = 5198 gπml),,480 h (20 d), gπml ( 2),, 015 h (C max = gπml),, 6 h (C = 8104 gπml),,480 h (20 d), gπml,528 h (22 d), ( 3),, 1 h (C max = gπml),,3 h 6 h, 12 h (C max = gπ ml), 2 96 h (4 d), 96 h(4 d),576 h(24 d),01021 gπ ml,600 h (25 d), ( 3),,24 h (C max = gπml),,600 h (25 d), gπml 3,,, 9 h ( C max = gπml),96 h (4 d) (C max = gπml),,,240 h (10 d),,600 h (25 d), gπml ( 3) 2 (25 ) Fig. 2 The hemolymph concentration of DIF in E. sinensis following a single oral gavage of 20 mgπkg 214 DAS, 1,,,

5 16 Chinese Journal of Zoology 44 3 (25 ) Fig. 3 The muscle, hepatopancreas, spermary, and ovary concentration of DIF in E. sinensis following a single oral gavage of 20 mgπkg Parameter 1 Table 1 Pharmacokinetic parameters of DIF in tissues of E. sinensis Hemolymph Muscle Tissue Hepatopancreas Spermary C max ( gπml) T max (h) t 1Π2 (h) t 1Π2 (h) t 1Π2 ka (h) V d (LΠkg) CL s (LΠh kg) AUC ( gπml h) T lag (h) Ovary 215, 4 5, 6 h,,12 48 h,,96 h,,,72 h (3 d),, 96 h (4 d), ; 48 h,144 h (6 d) 4, gπ ml gπml gπml gπml

6 2 : gπml,, 360 h (15 d), 360 h (15 d), 576 h (24 d),, h (24 25 d), gπml ( 5) 4 (25 ) Fig. 4 The hemolymph concentration of SAR in E. sinensis following a single oral gavage of 20 mgπkg 5 (25 ) Fig. 5 The muscle, hepatopancreas, spermary, and ovary concentration of SAR in E. sinensis following a single oral gavage of 20 mgπkg 3 311,, [3 9 ], ( Sus domestica) [4 ] ; ( Gallus gallus) [6 ] ; 20 ( Carassius auratus) [9 ], [6 ] ;10 [9 ],,,,

7 18 Chinese Journal of Zoology 44 [10 ], (9 h 96 h),, C max T max t 1Π2ka mgπkg [9 ], t 1Π2ka 0154 h, C max gπml, T max 2121 h10 mgπkg [6 ], t 1Π2ka 1146 h, C max 110 gπml, T max 4134 h5 mgπkg [4 ], t 1Π2ka 0154 h, C max 2129 gπml, T max 1141 h 20 mgπkg, t 1Π2ka h, C max gπml,t max 015 hc max, (T max ) ( Capra hircus),, AUC V d 20 mgπkg [9 ], 20,AUC gπml h,v d 4102 LΠkg ; 10,AUC gπml h,v d 2102 LΠkg 5 mgπkg [7 ],,AUC gπml h,v d 1168 LΠ kg ;,AUC gπml h ;,AUC gπml h [6 ] 10 mgπkg,auc gπml h,v d 3110 LΠ kg ;,AUC gπml h ;, AUC gπml h [4 ] 5 mgπkg,auc gπml h, V d 4191 LΠkg ;, AUC gπml h ;, AUC gπml h, 20 mgπkg, AUC gπml h gπml h gπml h gπml h gπml h, (AUC) V d 3117 LΠkg t 1Π2 CL s [4 ] 5 mgπkg t 1Π h h h,cl s 012 LΠh kg [6 ] 10 mgπkg, t 1Π26111 h, CL s 0137 LΠh kg [7 ] 5 mgπkg t 1Π h h h, CL s 0121 LΠh kg [9 ] 20 mgπkg, 10 20, CL s 0101 LΠh kg LΠh kg,20 t 1Π h,, t 1Π h h h h h,, ; CL s LΠh kg 0104 LΠh kg LΠh kg LΠh kg LΠh kg,,,,, [11 ],,,,

8 2 : 19, 312,, [3 ] ( Canis f amiliaris) [12 ],, C max gπml,, 5, C max gπml gπml gπml gπml gπml,, 3128 % 9123 % % % %,,, [13 15 ], 4 4,,,, ( Oryctolagus cuniculus) [16,17 ] (unhomogeneous),,,, 313, (MRL), 800 gπkg, 300 gπkg, 600 gπkg, 100 gπkg ; 30 gπkg, : 240 h (10 d), 576 h (24 d),576 h (24 d),,,(100 gπ kg), 24 d [ 1 ],..,2004,9(3) : [ 2 ].. :,2005, [ 3 ] Granneman G R, Snyder K M, Shu V S. Difloxacin metabolism and pharmacokinetics in humans after single oral doses. Antimicrobial Agents and Chemotherapeutics, 1986, 30 (3) : [ 4 ],,..,2003,36 (7) : [ 5 ] Garcia M A, Solans C, Aramayona J J, et al. Simultaneous determination of difloxacin and its primary metabolite sarafloxacin in rabbit plasma. Chromatographia,2000,51 : [ 6 ],,..,2004,34 (6) : [ 7 ] Marin P, Fernandez2Varon E, Escudero E, et al. Pharmacokinetics after intravenous, intramuscular and subcutaneous administration of difloxacin in sheep. in Veterinary Science,2007, 83 : Research [ 8 ] Chu D T W, Grannerman G. Difloxacin metabolian and pharmacokinetics in some animals after single oral doses. Vet Pharmacol Thera,2001,24(suppl 2) : [ 9 ] Ding F K, Cao J Y, Ma L B, et al. Pharmacokinetics and Commission Regulation of EEC, No. 2377Π90. Modified in the Reg. 2908Π00 Brussels,2000. Commission Regulation ( EC) No 508Π1999. Official Journal of the European Communities,1999, J

9 20 Chinese Journal of Zoology 44 tissue residues of difloxacin in crucian carp ( Carassius auratus) after oral administration. Aquaculture, 2006,256 : [10 ],..,2007,28(1) :1 3. [11 ],,,.,2004,8 ( ) : [12 ] Heinen E. Comparative pharmacokinetics of enrofloxacin and difloxacin as well as their main metabolites in dogs. Compendium on Continuing Education for the Practicing Veterinarian, 1999, 21(suppl) :12 18 [13 ],,..,2004,28 ( ) : [14 ] Tang J, Yang XL, Zheng Z, et al. Pharmacokinetics and the active metabolte of enrofloxacin in Chinese mitten2handed crab ( Eriocheir sinensis). Aquaclture,2006,260 : [15 ],,.., 2007,14(4) : [16 ],,..,1992,13 (2) : [17 ],,..,2001,17(2) : ,( E, N),() 2 ( Garrulax monileger) 20 m,15 min,,, ( G. pectoralis),5,,,, ;, , 10, ( G. berthemyi) ,,,, (Passeriformes) (Timaliidae) (,2006),,3, , ( ; )

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