磺胺甲噁唑在罗非鱼体内的药代动力学及组织浓度研究

研究了(19±1)℃水温条件下,以100 mg/kg剂量单次口腔灌药后,磺胺甲噁唑(SMZ)在罗非鱼的肌肉、血液、肝脏组织中的残留和消除规律.各组织中药物浓度由高效液相色谱法测得.研究结果表明,罗非鱼血液中的药物浓度符合一级吸收一室开放模式;消除相半衰期T1/2k8.70 h,吸收相半衰期T1/2kα0.94 h,达峰时间Tp3.38 h,达峰浓度Cmax18.41 μg/mL.建议SMZ在罗非鱼上的休药期为10 d.     

土霉素在锯缘青蟹体内的药物代谢和消除规律

采用高效液相色谱法检测土霉素,研究土霉素口灌给药途径下在锯缘青蟹体内的药代动力学。锯缘青蟹口灌给药土霉素50 mg/kg后,其血浆、肌肉和肝胰脏中的药峰浓度分别为16.78±1.98 mg/L、9.39±2.12μg/g和32.12±6.12μg/g,达峰时间分别为4 h、8 h和4 h。血浆中土霉素浓度-时间关系曲线符合一级吸收的二室开放动力学模型。土霉素在锯缘青蟹体内分布广泛,其表观分布容积(Vd)为2.129 L/kg;分布半衰期(t1/2α)和消除半衰期(t1/2β)分别为3.200 h和47.856 h,总体清除率(CLs)为0.063 mL/(kg.h)。肌肉和肝胰脏中土霉素浓度与时间关系的药动学参数采用统计矩原理分析,其消除半衰期(t1/2 z)分别为60.145 h和71.009 h,总体清除率(CLz)分别为0.054 g/(kg.h)和0.037 g/(kg.h)。土霉素在精巢和卵巢中达峰时间分别为8 h和12 h,峰浓度分别为9.83μg/g和10.26μg/g。给药后24 d时,血浆、肌肉、肝胰脏、精巢和卵巢中土霉素含量都已低于0.10μg/g。土霉素在锯缘青蟹体内消除比较缓慢。     

复方磺胺嘧啶口灌给药在拟穴青蟹(Scylla paramamosain)体内药动学和组织分布与消除

研究了水温为(27±1)℃、盐度为10条件下,单剂量(100 mg/kg)口灌给药复方磺胺嘧啶(磺胺嘧啶SD:甲氧苄啶TMP=5:1)后,SD和TMP在拟穴青蟹(Scylla paramamosain)体内的药动学以及在肌肉、肝胰腺和鳃组织中的分布和消除规律.结果显示,拟穴青蟹口灌复方磺胺嘧啶后,血淋巴中SD和TMP药物浓度-时间关系曲线均符合一级吸收二室模型,SD和TMP的峰浓度(Cmax)分别为49.56 mg/L和2.79 mg/L,药时曲线下面积(AUC)分别为1417.6 mg/L.h和82.7 mg/L·h;肝胰腺是SD和TMP峰浓度最高的组织,其Cmax分别为59.36 mg/kg和74.82 mg/kg.由此可见,大量TMP蓄积在肝胰腺中,进入血液循环的TMP很少.在鳃组织中,SD和TMP的Cmax分别为51.89 mg/kg和42.58 mg/kg,消除半衰期分别为23.28 h和25.29 h;鳃组织中药物浓度比较高,且消除速度较快,推测其在药物代谢中承担着消除功能.在肌肉中,SD和TMP的Cmax分别为44.95 mg/kg和10.09 mg/kg,消除半衰期分别为25.09 h和35.08 h.以0.1 mg/kg和0.05 mg/kg分别为SD和TMP的最高残留限量(MRL),95％置信区间,推算SD和TMP在拟穴青蟹肌肉中的理论休药期分别为290.6 h和302.8 h,在肝胰腺中分别为340.4 h和377.0 h.     

烟酸诺氟沙星和乳酸诺氟沙星在松浦镜鲤体内的药动学比较

应用高效液相色谱(HPLC)技术研究以相同浓度(30mg/kg)烟酸诺氟沙星和乳酸诺氟沙星对松浦镜鲤Cyprinus carpio specularis口灌给药后,药物在试验鱼血液、肝胰脏、肾脏中的药动学特征。相同给药剂量下,烟酸诺氟沙星和乳酸诺氟沙星在松浦镜鲤血浆中的血药浓度和时间关系均为一级吸收二室开放模型,吸收半衰期(t_(1/2ka))分别为0.061h、0.043h,消除半衰期(t_(1/2β))分别为29.969h、14.972h,达峰时间(T_(max))分别为0.327h、0.272h,达峰浓度(C_(max))分别为6.247mg/L、13.423mg/L,药时曲线下面积(AUC)分别为53.015mg·h/L、89.907mg·h/L,表观分布容积(V_d)分别为4.347L/kg、2.084L/kg。结果表明:在相同给药剂量下,乳酸诺氟沙星的吸收和消除速率均快于烟酸诺氟沙星,药物种类显著影响药动学特征。     

中药诃子的主要成分没食子酸在异育银鲫体内药物代谢动力学研究

在(20±1)℃的水温条件下,以77 mg/kg的单剂量,给异育银鲫(Carassius auratus gibelio)口灌诃子(Fructus chebulae)水剂,以诃子中的主要成分没食子酸为检测目标,用高效液相色谱法(HPLC)检测给药后各个时间点的血药浓度。结果显示:最低检测限为0.01μg/mL,线性范围为0.01～84.00μg/mL。诃子在异育银鲫体内的药动学过程符合一级吸收二室开放房室模型(1/C/C),其药物动力学方程为C=39.237e-0.320t+4.814e-0.006t,主要药动学参数为:吸收速率常数(Ka)为0.56 h-1,吸收半衰期(t1/2ka)为1.238 h,分布半衰期(t1/2α)为2.164 h,消除半衰期为(t1/2β)为119.369 h,达峰时间(Tmax)为4 h,最大血药浓度(Cmax)为11.024μg/mL,血药浓度-时间曲线下面积(AUC(0-∞))=674.89μg.h/mL,延滞时间(TL)为0.286 h,药物平均滞留时间(MRT(0-∞))=113.626 h,总体消除率(CLs)为0.112 L/(kg.h),表观分布容积(Vd)为13.713 L/kg。这些参数表明,异育银鲫口灌诃子后,能比较迅速被吸收,并且在血浆中维持较长的时间,具有较好的应用价值基础。     

噁喹酸在凡纳滨对虾体内药动学和对弧菌的体外药效

采用高效液相色谱法,研究了复方噁喹酸粉药饵投喂在凡纳滨对虾体内药动学和组织中消除规律,同时检测了噁喹酸对对虾源弧菌的最小抑菌浓度(MIC),建立了药动/药效(PK/PD)关系,提出了用药方案和休药期建议。结果显示,复方噁喹酸粉拌饵投喂给药,噁喹酸给药剂量为30 mg/kg(体质量),凡纳滨对虾血浆噁喹酸浓度—时间关系曲线均符合一级吸收二室开放动力学模型。血淋巴中噁喹酸达峰浓度(Cmax)、达峰时间(Tmax)、曲线下面积(AUC0-24)和消除半衰期(t1/2z)分别为14.70 mg/L、2 h、244.6 mg/(L·h)和18.56 h;肌肉、肝胰腺和鳃的峰浓度(Cmax)分别为4.11、17.20和7.01 mg/kg,消除半衰期(t1/2z)分别为10.71、12.31和16.75 h。噁喹酸对132株弧菌的MIC主要分布在0.15~1.25μg/m L,MIC50和MIC90分别为0.62和1.25μg/m L。PK/PD相互关系参数Cmax/MIC90和AUC0-24/MIC90分别为11.76和195.7。研究表明,噁喹酸以30 mg/(kg体质量)剂量药饵给药,凡纳滨对虾能很好地吸收噁喹酸,可以有效地防治弧菌引起的细菌性疾病。     

3种磺胺类药物在中国对虾(Fenneropenaeus chinensis)体内的药代动力学特征

采用高效液相色谱法研究了3种磺胺类药物在中国对虾体内的药物代谢动力学特征,这3种磺胺类药物包括磺胺二甲嘧啶(SM2)、磺胺嘧啶(SD)及磺胺对甲氧嘧啶(SMD)。实验期间,中国对虾的养殖水温为(24.6±2.4)℃,单次口服3种磺胺类药物的剂量均为100 mg/kg。结果显示,3种磺胺类药物在中国对虾体内的血药经时过程均符合一级吸收二室开放模型,SM2的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为25.812 h、34.066 mg/L·h、94.553 L/kg、2.608 L/h·kg、2 h、1.07 mg/L;SD的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为46.446 h、45.39 mg/L·h、97.207 L/kg、1.504 L/h·kg、1 h、1.17 mg/L;SMD的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为66.296 h、65.917 mg/L·h、40.015 L/kg、0.763 L/h·kg、2 h、2.00 mg/L。结果表明,SMD在中国对虾体内分布比SM2、SD更广泛;中国对虾体内SM2的消除相半衰期最短,SD次之,SMD消除相半衰期最长;3种磺胺类药物在中国对虾体内72 h药物吸收量SMD最高,SD次之,SM2最低;且SMD药物清除率最低,SD次之,SM2药物清除率最高,所以口服3种磺胺类药物72 h中国对虾体内SMD残留最多,SD次之,SM2残留最少。SMD在中国对虾体内药效更加持久,故在不考虑使用成本及毒副作用等其他因素的前提下,比较这3种磺胺类药物的药物代谢动力学特征,更加推荐使用SMD。     

3种磺胺类药物在中国对虾(Fenneropenaeus chinensis)体内的药代动力学特征

采用高效液相色谱法研究了3种磺胺类药物在中国对虾体内的药物代谢动力学特征,这3种磺胺类药物包括磺胺二甲嘧啶(SM2)、磺胺嘧啶(SD)及磺胺对甲氧嘧啶(SMD)。实验期间,中国对虾的养殖水温为(24.6±2.4)℃,单次口服3种磺胺类药物的剂量均为100 mg/kg。结果显示,3种磺胺类药物在中国对虾体内的血药经时过程均符合一级吸收二室开放模型,SM2的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为25.812 h、34.066 mg/L·h、94.553 L/kg、2.608 L/h·kg、2 h、1.07 mg/L;SD的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为46.446 h、45.39 mg/L·h、97.207 L/kg、1.504 L/h·kg、1 h、1.17 mg/L;SMD的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为66.296 h、65.917 mg/L·h、40.015 L/kg、0.763 L/h·kg、2 h、2.00 mg/L。结果表明,SMD在中国对虾体内分布比SM2、SD更广泛;中国对虾体内SM2的消除相半衰期最短,SD次之,SMD消除相半衰期最长;3种磺胺类药物在中国对虾体内72 h药物吸收量SMD最高,SD次之,SM2最低;且SMD药物清除率最低,SD次之,SM2药物清除率最高,所以口服3种磺胺类药物72 h中国对虾体内SMD残留最多,SD次之,SM2残留最少。SMD在中国对虾体内药效更加持久,故在不考虑使用成本及毒副作用等其他因素的前提下,比较这3种磺胺类药物的药物代谢动力学特征,更加推荐使用SMD。     

诺氟沙星在大菱鲆体内药代动力学及残留消除规律

利用高效液相色谱法分别测定了单次和多次混饲口灌大菱鲆诺氟沙星(NFLX)后鱼体主要组织中的NFLX含量。通过MCP-KP药动学程序对NFLX在大菱鲆体内的药代动力学及残留消除规律进行了分析研究。结果表明,以30mg/kg的剂量单次混饲口灌大菱鲆,NFLX在大菱鲆体内的达峰时间(Tmax)为2h,血、鳃、肾脏、肝脏、肌肉的达峰浓度(Cmax)分别为:8.365、7.519、1.871、6.485和4.060μg/g;NFLX在组织中的消除半衰期(T1/2)由小到大依次为:肝脏8.18h<肌肉12.39h<鳃丝15.29h<血液23.22h<肾脏23.25h。连续5d以30mg/kg的剂量混饲口灌大菱鲆,消除半衰期(T1/2)由小到大依次为:肌肉74.88h<血液98.16h<肝脏186.43h<鳃192.12h<肾脏200.45h。以上研究表明,诺氟沙星在大菱鲆体内的吸收较为迅速,有利于疾病的预防和治疗用药。在组织中以肾脏中的残留最为显著。使用诺氟沙星进行大菱鲆疾病的预防和治疗时,至少停药30d后方可上市销售。     

甲砜霉素在大菱鲆体内的代谢及消除规律

为研究甲砜霉素(thiamphenicol)在大菱鲆(Scophthalmus maximus)体内的代谢动力学特征和残留消除规律,本研究采用液相色谱-串联质谱法检测甲砜霉素混饲口灌后在大菱鲆血浆、肌肉、肝脏和肾脏等样品中的时间-浓度变化。甲砜霉素以30 mg/kg的剂量单次混饲口灌,采集给药后48 h内的药时数据,并以DAS软件非房室模型进行分析,结果显示,甲砜毒素在大菱鲆血浆中达峰浓度(C_(max))和达峰时间(T_(max))分别为21.968μg/m L和9 h,药时曲线下面积[AUC_((0—∞))]为319.754 mg/(L·h),表观分布容积(Vz/F)为6.206 L/kg,平均滞留时间[MRT_((0—∞))]和消除半衰期(T1/2z)分别为33.984 h和45.841 h。甲砜霉素在大菱鲆的肌肉、肝脏和肾脏组织中达峰浓度(C_(max))分别至22.346、27.128和47.718μg/g;在肝脏中达峰时间较快(4 h),在肌肉和肾脏组织中均在9 h;在肾脏中的达峰浓度(C_(max)=47.718μg/g)和药时曲线下面积AUC(0-∞)最大,为517.768 mg/(L·h),表明肾脏对甲砜霉素的吸收能力最高;在肝脏中的平均滞留时间[MRT_((0—∞))=36.565 h]最长,消除半衰期T1/2z为42.370 h,即给药后48 h内甲砜霉素在肝脏中的消除较慢。甲砜霉素以60 mg/kg的高剂量单次给药后,采集30 d内的药时数据并以WT程序进行计算,结果显示甲砜霉素在大菱鲆血浆、肌肉、肝脏和肾脏中的理论休药期分别为8.90、10.64、18.19和23.95 d。本研究结果可为甲砜霉素在大菱鲆中的合理应用提供科学依据。     

土霉素在奥尼罗非鱼体内的药动学研究

在(21±1)℃的水温条件下,以50 mg/kg的单剂量,分别给奥尼罗非鱼(Oreochromis aureus×O.niloticus)水剂口灌和混饲口灌土霉素,用高效液相色谱法(HPLC)检测给药后各个时间点的血药浓度。结果显示:最低检测限为0.005μg/mL,线性范围为0.005~4μg/mL。水剂口灌组和混饲口灌组的药时数据均符合具时滞的二室开放动力学模型,水剂口灌组的动力学方程为:Ct=0.231e-0.028(t-0.010)+0.353e-0.011(t-0.010)-0.584e-0.468(t-0.010),混饲口灌组动力学方程:Ct=0.839e-0.057(t-0.459)+0.442e-0.013(t-0.459)-1.281e-0.282(t-0.459)。水剂口灌组及混饲口灌组主要药动学参数分别为:吸收半衰期(t1/2ka)为1.481 h,2.458 h;分布半衰期(t1/2α)为24.834 h,12.193 h;消除半衰期(t1/2β)为60.312 h,51.533 h;达峰时间(Tmax)为7.230 h,8.221 h;最大血药浓度(Cmax)为0.494μg/mL,0.796μg/mL;血药浓度-时间曲线下面积(AUC)=37.74μg.h/mL,43.075μg.h/mL。这些参数表明,水剂口灌比混饲口灌吸收快,分布和消除慢,在血液中达到峰浓度的时间更短,但峰浓度值比混饲口灌低。     

伊维菌素在鲫体内的药代动力学

以0.4 mg/kg的给药剂量进行口灌和肌肉注射给药,研究伊维菌素(IVM)在鲫体内的药代动力学。两种给药方式下,鲫组织中的IVM药—时曲线大都呈现多峰现象。肌肉注射给药后,药动学统计矩参数为Cmax=0.445 mg/L、Tmax=48 h、t1/2z=524.2 h、MRT(0-∞)=788 h、AUC(0-∞)=289.2(mg/L).h;口灌给药后,药动学统计矩参数为Cmax=0.264 mg/L、Tmax=8 h、t1/2z=153.9h、MRT(0-∞)=269.78 h、AUC(0-∞)=83.77(mg/L).h。两种给药方式相比,口灌组鲫对药物的吸收和清除均较快,而肌肉注射组鲫各组织中的药物浓度高,AUC值也较大。两种给药方式下,IVM在鲫各组织中AUC(0-600)值呈现相同的排列顺序,由大到小分别为性腺、血液、肾脏、肝胰脏、肌肉。IVM在鲫性腺和肾脏中均具有一定的蓄积作用,其主要表现为药物浓度高,MRT值大,且清除率低于血药的清除率,其中卵巢的积蓄作用最为明显。25℃的水温条件下,肌肉注射给药后,鲫休药期应不低于25 d;口灌给药后,鲫的休药期应不低于15 d。休药期与水温条件和给药剂量有关,因此在养殖生产过程中的休药期要根据实际情况适当调整。     

A single-dose pharmacokinetic study of oxolinic acid and vetoquinol,an oxolinic acid ester,in cod,Gadus morhua L., held in sea water at 8 degrees C and in vitro antibacterial activity of oxolinic acid against Vibrio anguillarum strains isolated from diseased cod

The pharmacokinetic properties of the antibacterial agent oxolinic acid and vetoquinol, the carbitol ester of oxolinic acid, were studied after intravenous (i.v.) and oral (p.o.) administration to 100-150 g cod, Gadus morhua L., held in sea water at 8 degrees C. Following i.v. injection, the plasma drug concentration-time profile showed two distinct phases. The distribution half-life (t1/2alpha) was estimated at 1.3 h, the elimination half-life (t1/2beta) as 84 h and the total body clearance (Cl(T)) as 0.047 L kg(-1) h(-1). The volume of distribution at steady state, Vd(ss) was calculated to be 5.5 L kg(-1), indicating good tissue penetration of oxolinic acid in cod. Following p.o. administration of oxolinic acid or vetoquinol, the peak plasma concentrations (C(max)) of oxolinic acid and the time to peak plasma concentrations (T(max) were estimated to be 1.2 and 2.5 microg mL(-1) and 24 and 12 h, respectively. The bioavailabilities of oxolinic acid following p.o. administration of oxolinic acid and vetoquinol were calculated to be 55 and 72%, respectively. The in vitro minimum inhibitory concentration (MIC) values of oxolinic acid against three strains of Vibrio anguillarum isolated from diseased cod were 0.016 microg mL(-1) (HI-610), 0.250 microg mL(-1) (HI-618) and 0.250 microg mL(-1) (HI-A21). Based on a MIC value of 0.016 microg mmL(-1) a single p.o. administration of 25 mg kg(-1) of oxolinic acid maintains plasma levels in excess of 0.064 microg mL(-1), corresponding to four times the MIC-value, for approximately 12 days. The analogous value for a single p.o. dose of 25 mg kg(-1) of oxolinic acid administered as vetoquinol was 13 days.     

Pharmacokinetics,optimal dosages and withdrawal time of florfenicol in Asian seabass (Lates calcarifer) after oral administration via medicated feed

Asian seabass (Lates calcarifer) is an economically important fish in Asian and Australian markets, but few pharmacokinetic (PK) data of antimicrobial drugs in this species is available. The present study investigated the PK behaviour of florfenicol (FF) through medicated feed in Asian seabass cultured at 25°C. The serum and muscle/skin concentrations of FF and its metabolite florfenicol amine (FFA) were determined by the HPLC-FLD method and analysed by one-compartmental model. The optimal dosages were determined by pharmacokinetic-pharmacodynamic (PK-PD) approach and the linear regression analysis was used to determine the withdrawal time (WDT). The PK study following a single oral administration of 15 mg/kg FF via medicated feed revealed that the absorption half-life (t_1/2Ka), elimination half-life (t_1/2K), peak concentration (C_max), area under the concentration-time curve (AUC), volume of distribution (Vd/F) and clearance (CL/F) were 1.47 h, 8.07 h, 8.61 μg/ml, 146.41 h·μg/ml, 1.19 L/kg and 0.102 L/kg/h, respectively. The muscle/skin concentration-time profile was similar to that of the serum, suggesting well distribution but only a small fraction of FF was metabolized to FFA. The optimal dosage for a minimum inhibitory concentration of 2 μg/ml was calculated as 13.38 mg/kg/day. The appropriate WDT after multiple oral medications with 15 mg/kg FF once daily for 7 days was determined as 8 days. Information obtained from the current study can potentially be applied for the treatment of bacterial diseases in farming Asian seabass.     

Pharmacokinetics and tissue distribution of oxytetracycline in carp, Cyprinus carpio L., following different routes of administration

Abstract. The objective of this pharmacokinetic study was to investigate absorption, distribution, elimination and bioavailability of oxytetracycline (OTC) in carp, Cyprinus carpio L ., after different routes of administration, OTC was administered intravenously (i.v.), intramuscularly (i.m.) and orally at 60 mg/kg body weight. OTC levels were determined in plasma and several tissues. Analysis of the plasma drug concentration-time curves following i.v. OTC injection revealed three distinct phases. A three-compartment open model was used to derive pharmacokinetic parameters. Compared to mammals, a very extended final elimination half-life was observed (139.8±38.1 h). Following i.m. OTC administration, C_max was 56.8±10.9μg OTC/ml at 14 h post-injection. The Vd area was 2.1 ± 0.66 1/kg. Extreme differences were observed with respect to bioavailability following i.m. and oral administration; approximately 80 and 0.6%, respectively. Following i.m. injection tissue OTC determinations revealed that the drug was accumulating in pronephros, bone tissue and scales. After 21 days the OTC concentrations were 2.9±0.8, 5.2±0.3 and 4.7±3.1 μg/ ml, respectively. In tissue samples from the dorsal region (muscle), including the injection site, OTC could not be demonstrated at that time. The pharmacokinetic data are discussed in relation to the susceptibility of the immune system of fish for modulation.     

Pharmacokinetics of sulfamonomethoxine in tongue sole (Cynoglossus semilaevis) after intravenous and oral administration

The pharmacokinetic profiles of sulfamonomethoxine (SMM) were investigated in flatfish tongue soles in the present study. After a single injection of SMM (40 mg/kg BW) to caudal vein of tongue sole at 20 °C, plasma drug concentration versus time data were best fitted to a three-compartment model, characterized with 0.2, 5.7, and 80.4 h for the half-life (t _1/2) of fast distribution, slow distribution, and elimination, respectively. The apparent volume of distribution was 0.1 L/kg, and the body clearance was 0.03 L/h/kg. After oral administration of SMM (200 mg/kg BW) to tongue soles at 20 °C, plasma drug concentrations were best fitted to a two-compartment model, of which the mean half-life of absorption (t _1/2ka) and elimination (t _1/2β ) were 1.7 and 95.7 h, respectively. The maximal absorption concentration (C _max) was estimated as 58 mg/L at 2.5 h, and the mean systemic bioavailability (F) was 39.5 % in tongue soles after oral administration.