溴泰君与阿霉素单用和联合应用在Beagle犬的毒代动力学研究

目的:研究溴泰君(W198)在Beagle犬体内毒代动力学,为临床试验提供依据。方法:采用HPLC紫外或荧光检测方法测定Beagle犬静脉注射溴泰君、阿霉素以及溴泰君与阿霉素联合给药后生物样品中溴泰君和阿霉素的浓度。结果:Beagle犬静脉注射溴泰君15 mg·kg-1·d-1,第1次、第3次、第72次给药后的血清药物浓度-时间曲线下的面积(AUC0-24h)分别为6.15±0.66、26.55±9.43和33.63±2.31 mg·h-1·L-1。Beagle犬静脉注射阿霉素每次1.5mg·kg-1,第1次和第3次给药后的血清药物AUC0-24h分别为0.70±0.21和1.19±0.19mg·h-1·L-1。溴泰君与阿霉素联合给药时,溴泰君连续给药3次、阿霉素给药1次和溴泰君连续给药39次、阿霉素给药3次后溴泰君的血清药物AUC0-24h分别为 25.52±6.04和42.60±4.14 mg.h-1·L-1;阿霉素的血清药物AUC0-24h分别为0.39±0.05和0.77±0.19 mg·h-1·L-1。结论:溴泰君和阿霉素连续多次给药后药物在动物体内均有明显蓄积作用。联合给药后溴泰君对阿霉素的消除似有促进作用,揭示溴泰君可以使阿霉素的系统暴露量减低,有利于降低阿霉素的毒性。     

Balofloxacin在小鼠,大鼠和狗体内药代动力学

balofloxacin(CAS127294-70-6,Q-35),化学名1-环丙基-6-氟-1,4-二氢-8-甲氧基-7-(3-甲氨哌-1)-4氧喹啉-3-羧酸二水合物,是一种广谱抗革兰阳性和阴性菌的喹诺酮类药物,Nakagawa等对balofloxacin在小鼠、大鼠和狗体内药代动力学进行了研究.     

溴泰君在大鼠的组织分布和排泄

目的研究溴泰君(W198)在大鼠的组织分布和排泄，为临床试验提供依据。方法用HPLC紫外检测方法测定大鼠iv W198后生物样品中的药物含量。结果大鼠iv W198 20 mg·kg^-1后组织的药物含量远高于相同时间的血清药物浓度。药物主要分布在肺，其次在肾、心、肝等组织,大部分组织的药物含量于给药后0.25 h最高，给药后2 h显著下降，至24 h均缓慢下降；大鼠iv W198 20 mg·kg^-1后从尿、粪(0-96 h)和胆汁(0-24 h)中排泄的原型药物分别占给药总量的0.150%，2.1%和0.063%。结论W198主要分布于肺组织中。从尿、粪和胆汁中排泄的原型药物很少。     

艾普斯特在大鼠和犬的药代动力学

目的　研究艾普斯特(epristeride)在动物体内药代动力学,为临床试验提供依据。方法　采用HPLC方法测定生物样品中药物浓度。结果　大鼠po epristeride 10,20和40 mg.kg^-1后,3个剂量的血清药物浓度出现明显双峰。Beagle犬po 10　mg.kg^-1后血药浓度未出现明显双峰。 大鼠po 20　mg.kg^-1后3 h, 大部分组织中含量高于药后6 h含量; 药后24 h内尿和粪的排泄量分别占给药量的0.09%和42.9%, 12 h内胆汁排泄的主要为代谢产物, 原型药物仅为给药量的0.14%。本品蛋白结合率为92.3%。结论　Epristeride在10～40 mg.kg^-1范围内呈现一级动力学特征, C_max, AUC均与剂量呈正相关。药物在组织脏器中分布广泛, 主要经粪和胆汁排泄。     

奥拉西坦在大鼠和小鼠的药代动力学研究

目的： 研究奥拉西坦(ORC)在大鼠和小鼠的药代动力学。方法： 采用HPLC法测定生物样品中ORC浓度, 在大鼠和小鼠进行其药代动力学、吸收、分布、排泄试验。结果： 大鼠灌胃给ORC 100,200和400 mg.kg^-1后表明, 本品po吸收速率快,达峰时间短,药物自血清消除较快。小鼠1次ig给药100 mg.kg^-1后,80%以上药物在给药后3 h内由消化道消失;药物吸收后能分布到各种组织脏器, 给药后36 h累计尿排泄原形药物量约为药物剂量的80%; 蛋白结合率低,平均结合率为10.5%。结论： 奥拉西坦是一吸收快、消除快、主要以原形药物由尿排泄、蛋白结合率低的药物。     

雷公藤内酯酮在大鼠体内的药代动力学和体内处置研究

采用RP HPLC法,测定给药后不同时刻大鼠血浆中雷公藤内酯酮的浓度。大鼠iv0.7,1.4,2.8mg·kg^-1雷公藤内酯酮后,血浓数据用PKBP-N1程序拟合,药物动力学模型为两室开放模型,T_1/2α为0.167～0.195h,T_1/2β为4.95～6.49h,曲线下面积(AUC)与剂量成正比,清除率(CLs)与剂量无关。非房室模型统计矩计算的结果表明,3剂量平均驻留时间MRT为3.26～5.14h。大鼠iv雷公藤内酯酮后,在大鼠体内分布广泛,其中以肺和肝药物浓度最高,心、肾、脾和肌肉次之,睾丸、胃肠道和脑中最低。iv雷公藤内酯酮后,经尿和胆汁排泄的原型药物较少。雷公藤内酯酮的血浆蛋白结合率约为75%。     

磷酸川芎嗪在狗和大鼠的药代动力学和体内命运

本文研究犬一次静注、肌注和口服磷酸川芎嗪的药代动力学和生物利用度并与盐酸川芎嗪进行比较。观察到磷酸川芎嗪属一级消除动力学,按一房室开放模型计算其各项动力学参数。证明静注、肌注和口服磷酸川芎嗪吸收较快、消除迅速。但肌注磷酸川芎嗪比盐酸川芎嗪吸收较好,血浆清除较慢,半衰期较长,肌注的生物利用度为81.68%。磷酸川芎嗪口服吸收较规律。大鼠ig磷酸川芎嗪吸收良好,组织分布广泛,以肝组织中含量最高。36 h内原形药从粪便和尿中共排出剂量的1.40%。     

环氧司坦在大鼠的药代动力学

大鼠灌胃(ig)环氧司坦三种剂量50,100及200 mg·kg^-1后,测定12 h的血药浓度,根据各鼠血药浓度—时间数据拟合曲线,均呈一室动力学模型。其Ka分别为0.578 h^-1,0.553 h^-1,0.439 h^-1;K分别为0.308 h^-1,0.282 h^-1,0.224 h^-1;T_1/2分别为2.27 h,2.54 h,3.12 h;AUC分别为786.89,1644.43和3335.35 μg·h^-1·ml^-1。组织中以肾上腺、肝、胃肠、生殖器(子宫与卵巢)为高,其次是肾、心、脑、肺、脾,高峰浓度在3 h左右,与血药浓度分布情况一致。三种剂量的血浆蛋白结合率均在90%左右,结合率与给药剂量无关。原形药在胆汁、尿及粪便中排泄百分率甚少。提示大部分药物可能在体内进行转化。     

萘哌地尔在大鼠体内的药代动力学

为全面了解萘哌地尔(Naf)在大鼠体内的代谢过程,用反相HPLC-UV法,给大鼠ig10,20,30mg·kg^-1Naf后,测定在不同时间各组织和体液中Naf的含量。结果表明,Naf在大鼠体内药代动力学为二室模型,T_1/2α为0.47～1.01h,T_1/2β为4.78～7.08h,达峰时间T(peak)为0.42～0.90h,Cmax,AUC随剂量升高而增大。给药后15min,肠壁组织浓度最高,其次为肝、肺;2h以后,除睾丸、卵巢和子宫外,其余组织药物浓度逐渐降低。尿、粪及胆汁中原形药总排出量不足给药量的1%,提示Naf在大鼠体内有首过效应及代谢物生成。在100～500mg·ml^-1浓度范围内,Naf血浆蛋白结合率为82%～97%。     

Pharmacokinetics of 14C-DMPS (sodium-1,3 14C-2,3-dimercaptopropane-l-sulphonate) in beagle dogs

The pharmacokinetics of labelled DMPS (sodium-1,3 ¹⁴C-2,3-dimercaptopropane-1-sulphonate) have been studied in four beagle dogs following bolus intravenous injection (65-7 μmolkg^?1) and oral administration (197μmol kg^?1). Following intravenous injection the main kinetic parameters were t_1/2 = 43min, V_β = 160 ml kg^?1, and plasma clearance Cl_p = 2.6ml min^?1 kg^?1. Following oral administration ¹⁴C-DMPS is rapidly absorbed with peak concentrations (478 ± 25 umol 1^?1) measured after 30–45 min. About 60 per cent of the oral dose was absorbed. Estimates of t_1/2, V_β, and Cl_p after oral administration were in close agreement with the values obtained in the intravenous study. ¹⁴C-DMPS is eliminated from the body by the kidneys. About 70 per cent of ¹⁴C-DMPS in dog plasma are bound to proteins. Binding is even higher in plasma from rat and man.     

蝙蝠葛碱在犬体内的药代动力学和药效动力学研究

目的　应用药动学药效学结合模型方法研究蝙蝠葛碱在犬体内的药代动力学和药效动力学之间的关系。方法　4只beagle犬给蝙蝠葛碱6mg·kg-1静脉注射后,分时取血及行心电、血压及血流动力学变化观察。采用反相高效液相紫外法测定血浆中蝙蝠葛碱的浓度。结果　蝙蝠葛碱主要药动学参数T1 /2α,T1 /2β,Vd,AUC分别为(0 049±0 016)h,(2 .7±0. 6)h, (15. 8±3 5)L·kg-1和(1. 48±0. 17)mg·h·L-1。对Q Tc的最大延长率为( 25 5±9 4 )%;SBP,DBP,±(dp/dt)max的最大抑制率分别为( 23 .0±4. 9 )%,(21 .9±5. 9)%, ( 42. 8±6 .6 )%和( 39 .0±17 .1 )%。药理效应滞后于血药浓度10 ~15min。药理效应与效应室浓度之间的关系符合sigmoid Emax模型。结论　建立了蝙蝠葛碱在犬体内血药浓度、时间、药物效应三者之间的关系。     

丹七注射液中丹参素钠在Beagle犬体内药代动力学及生物利用度研究

目的研究丹七注射液中丹参素钠在Beagle犬体内的药代动力学。方法液相色谱-紫外光谱法,乙腈-1％的冰醋酸水溶液（8：92）为流动相,测定一次性静脉注射丹七注射液（28．4mg·kg^-1）和一次性口服丹七丸（114．7mg·kg^-1）后Beagle犬血浆中丹参素钠含量。采用BAPP2．3生物利用度数据处理通用程序中的模型拟合与统计矩法计算药物的药代动力学参数。结果静注和口服丹七制剂中的丹参素钠在Beagle犬体内的药代动力学均符合二室模型,T1/2为0．573、2．258h,AUC分别为29．792、77．84h·μg·ml^-1,口服生物利用度为63．8％。结论丹七注射液中丹参素钠在Beagle犬体内呈快吸收慢消除动力学特征。     

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs

Summary N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 was 0.2 hours (12 minutes) and t1/2 was 0.75 ± 0.1 hours (45 ± 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.     

Kinetics of ajmaline disposition and pharrnacologic response in beagle dogs

Pharmacokinetics and pharmacodynamics of ajmaline were studied in four healthy dogs after intravenous administration of the drug at the infusion rate of 1.0 mg/min for 45 min. Ajmaline exhibited a saturable binding to plasma protein. One kind of binding site was found in the range of observed drug concentrations and its binding capacity showed nearly threefold interindividual difference. The time course of ajmaline concentration in whole blood Cbcould be described by the two-compartment open model and the unbound concentration of ajmaline in plasma Pf wasestimated from Cbby using the hematocrit value and the parameters of plasma protein binding and erythrocyte partitioning. The pharmacologic responses to ajmaline were assessed by recording ECG, and the changes in PQ and QRS interval were studied in relation to ajmaline disposition. When ECG changes were related to the ajmaline concentration, a significant degree of hysteresis was observed. The relationship between the unbound drug concentration and the pharmacologic effect was analyzed by a combined pharmacokinetic-pharmacodynamic model, where the hypothetical effect compartment is connected to the Pfin the central compartment by a first-order process. This model allows estimation of the changes in PQ and QRS intervals after intravenous administration of ajmaline. By comparing the drug effect on PQ and QRS intervals, it was suggested that ajmaline distributes to the atrial and the ventricular tissue in a similar degree and causes a reduction in the conduction rate in both sites with similar activity.     

烟酸缓释胶囊在Beagle犬体内的药动学及生物等效性

目的 6只Beagle犬双周期双交叉单剂量口服烟酸受试制剂和参比制剂。方法用LC-MS/MS法检测血浆中药物浓度,计算两种制剂的药动学参数并进行等效性评价。结果受试胶囊和参比片剂的主要药动学参数为:Tmax(3.00±0.80)和(3.08±0.90)h,Cmax(5.13±0.52)和(4.85±0.64)mg·L-1,AUC0-t(43.85±7.41)和(51.30±6.50)mg·L-1.h-1,AUC0-∞(47.25±5.35)和(49.19±4.21)mg·L-1.h-1。受试制剂的相对生物利用度F为(96.0±6.7)%。结论表明两种制剂生物等效。     

3－酮－地索高诺酮在家兔体内的药物动力学

以高效液相色谱分析法测定按２ｍｇ·ｋｇ－１剂量给家兔皮下注射３－酮－地索高诺酮后０．２５～２４ｈ的血药浓度，其血药浓度－时间曲线符合二室开放模型，药物动力学方程为Ｃ＝２５７．０７ｅ－０．７１ｔ＋４２．２３ｅ－０．０５ｔ－２９９．３０ｅ－０．９３ｔ主要药物动力学参数：Ｔｋａ０．７８±０．１７ｈ，Ｔα１．２０±０．３０ｈ，Ｔβ１２．０９±４．１８ｈ，ＡＵＣ１３１２．９０±３８７．４５μｇ·ｈ￣（－１）·Ｌ￣（－１），Ｔ＿（ｍａｘ）１．６９±０．３９ｈ，Ｃ（ｍａｘ）＝１２８．２１±５０·７１μｇ·Ｌ￣（－１），Ｖ／Ｆ９．５０±４．３９Ｌ·ｋｇ（－１）。采用平衡透析法测得３－酮－地索高诺酮与兔血浆蛋白的结合率在８１．０９％～８４．６０％之间。     

3－酮－地索高诺酮在家兔体内的药物动力学

以高效液相色谱分析法测定按２ｍｇ·ｋｇ－１剂量给家兔皮下注射３－酮－地索高诺酮后０．２５～２４ｈ的血药浓度，其血药浓度－时间曲线符合二室开放模型，药物动力学方程为Ｃ＝２５７．０７ｅ－０．７１ｔ＋４２．２３ｅ－０．０５ｔ－２９９．３０ｅ－０．９３ｔ主要药物动力学参数：Ｔｋａ０．７８±０．１７ｈ，Ｔα１．２０±０．３０ｈ，Ｔβ１２．０９±４．１８ｈ，ＡＵＣ１３１２．９０±３８７．４５μｇ·ｈ￣（－１）·Ｌ￣（－１），Ｔ＿（ｍａｘ）１．６９±０．３９ｈ，Ｃ（ｍａｘ）＝１２８．２１±５０·７１μｇ·Ｌ￣（－１），Ｖ／Ｆ９．５０±４．３９Ｌ·ｋｇ（－１）。采用平衡透析法测得３－酮－地索高诺酮与兔血浆蛋白的结合率在８１．０９％～８４．６０％之间。     

Pharmacokinetics of magnesium lithospermate B after intravenous administration in beagle dogs

AIM: To develop a specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the phar-macokinetic study of magnesium lithospermate B (MLB), and study the pharmacokinetics of MLB after iv administration in beagle dogs. METHODS: Each beagle dog was iv administered MLB 3, 6, and 12 mg/kg random. The serum drug concentration was determined by specific liquid chromatography-tandem mass spectrometry (LC-MS/ MS) assays. The pharmacokinetic parameters were calculated by Drug and Statistics version 1.0 program. RESULTS: The calibration curve for MLB was linear over a range of 16-4096μg/L with coefficients of correlation >0.999. The intra- and inter-day precisions (CV) of analysis were <10 %, and accuracy ranged from 90 % to 113 %. After iv administration of MLB at the doses of 3, 6, and 12 mg/kg, the C0 values for MLB were estimated to be of 24, 47, and 107 mg/L, respectively. The AUC increased with the increasing doses for iv administration, and the mean AUC0-t values were 109.3, 247.9, and 5     

Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat

1. Valspodar is a P-glycoprotein inhibitor widely used in preclinical and clinical studies for overcoming multidrug resistance. Despite this, the pharmacokinetics of valspodar in rat, a commonly used animal model, have not been reported. Here, we report on the pharmacokinetics of valspodar in Sprague–Dawley rats following intravenous and oral administration of its Cremophor EL formulation, which has been used for humans in clinical trials.

2. After intravenous doses, valspodar displayed properties of slow clearance and a large volume of distribution. Its plasma unbound fraction was around 15% in the Cremophor EL formulation used in the study. After 10?mg kg^?1 orally it was rapidly absorbed with an average maximal plasma concentration of 1.48?mg l^?1 within approximately 2?h. The mean bioavailability of valspodar was 42.8%.

3. In rat, valspodar showed properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A.