Cyclosporine pharmacokinetics in rats and interspecies comparison in dogs, rabbits, rats, and humans

The pharmacokinetics of cyclosporine, a potent immunosuppressive agent, are described for rats given 5 mg/kg iv, measuring blood concentrations by a specific HPLC method. Cyclosporine followed first-order kinetics and blood concentrations vs. time data were adequately described by a three-compartment open model system. The mean half-life of the lambda 1 phase was 0.11 hr, that of the lambda 2 phase was 1.82 hr, and the half-life of the estimated lambda 3 phase was 23.79 hr. The mean apparent volume of distribution and Vss were 5.69 and 4.54 liters/kg, respectively. The mean blood total body clearance was 3.38 ml/min/kg. The literature was reviewed to obtain comparable data from other mammalian species, and satisfactory kinetic information was found for humans, dogs, and rabbits. Interspecies variants in physiological parameters and cyclosporine pharmacokinetics were considered and treated as a property and consequence of body size (allometry), nullifying anatomical and physiological differences between species. A relationship between pharmacokinetic time (a variable in terms of chronological time) and body weight was found. It is suggested that the metabolic capacity (based on liver weight) to eliminate cyclosporine is similar in humans, rabbits, and rats, whereas the dog showed a potentially double capacity to metabolize the drug. However, metabolic and pharmacodynamic studies are also needed to predict toxicity accurately among species.     

注射用灯盏花素脂质体在Beagle犬体内的药代动力学

目的制备灯盏花素脂质体，研究灯盏花素脂质体在Beagle犬体内的药代动力学。方法采用双周期交叉试验法，6只Beagle犬分别单剂量(以灯盏乙素计为28 mg/只)静脉注射自制灯盏花素脂质体和市售普通注射液，用反相高效液相色谱法测定不同时间血浆中灯盏乙素的浓度，采用3P97计算药代动力学参数，并进行统计学分析。结果脂质体和市售注射液的T_1/2α分别为(4.4±0.7) min和(1.8±1.3) min；T_1/2<>分别为(55±27) min和(28±23) min；V_c分别为(1 580±265) mL和(2 460±2 200) mL；CL_s分别为(88±10) mL·min^-1和(324±69) mL·min^-1； AUC_0-720分别为(363±42) μg·min·mL^-1和(102±19) μg·min·mL^-1。两种制剂的T_1/2α，CL_s及AUC_0-720经方差分析后均存在极显著或显著性差异。结论与市售普通注射液相比，灯盏花素脂质体Beagle犬静脉注射给药后，大大提高了血药浓度，显著改善了灯盏乙素原药的药代动力学性质，具有缓释作用。     

Species comparison of pharmacokinetics and metabolism of diltiazem in humans, dogs, rabbits, and rats

Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and related heart diseases. It is extensively metabolized into a host of metabolites, some of which have potent pharmacological activities. In this study, the pharmacokinetics and metabolism of DTZ was investigated in humans, dogs, rabbits, and rats after each species (n = 4 or 5) was given a single oral dose of DTZ. After the drug administration, blood and urine samples were collected for 12 and 48 hrs, respectively. DTZ and six of its metabolites were quantitated in our laboratory by HPLC. The results indicated that, in humans, the major metabolites in plasma were N-monodesmethyl diltiazem (MA), deacetyl diltiazem (M1), and deacetyl N-monodesmethyl diltiazem (M2). These metabolites were also detected in the plasma of dogs, rabbits, and rats. However, there were quantitative differences. For example, in the humans and dogs, MA was the most abundant metabolite in plasma, while M1 and M2 were most prominent in the rabbits and rats, respectively, and M2 was a relatively minor metabolite in dog plasma. Less than 5% of the dose was recovered as unchanged DTZ in the urine of all the tested species. The most abundant metabolites in urine appeared to be MA and deacetyl N,O-didesmethyl diltiazem, although there were considerable inter- and intra-species variations. Two additional metabolites were detected in the urine of the humans, dogs, and rabbits, but not in the rats. They were tentatively identified as O-desmethyl diltiazem and N-O-didesmethyl diltiazem, using electron impact and ammonia chemical ionization mass spectrometry.(ABSTRACT TRUNCATED AT 250 WORDS)     

灯盏花素脂质体对大鼠脑缺血再损伤的保护作用

目的 观察灯盏花素脂质体对脑缺血再灌注大鼠脑损伤的保护作用。方法 采用线栓法构造大鼠大脑动脉脑缺血再灌注损伤模型，观察大鼠神经功能障碍情况并进行评分，测定再灌注后缺血侧脑梗死范围及脑组织中超氧化物歧化酶、谷胱甘肽过氧化物酶的活性及丙二醛的含量。结果 灯盏花素脂质体能显著减少脑缺血再灌注损伤大鼠的脑梗死面积和减轻神经功能障碍，并抑制缺血脑组织中丙二醛的含量。提高脑组织中超氧化物歧化酶和谷胱甘肽过氧化物酶的活性。结论 灯盏花素脂质体对大鼠大脑缺血再灌注损伤有明显保护作用，具有良好的新药开发前景。     

Interspecies scaling of oleanolic acid in mice,rats, rabbits and dogs and prediction of human pharmacokinetics

This study was conducted to predict the pharmacokinetics of oleanolic acid in humans based on animal data by allometry and several species-invariant time methods. Oleanolic acid was injected intravenously to mice, rats, rabbit and dogs (dose 1 mg/kg). The serum concentration-time profiles of oleanolic acid were best described by bi-exponential equation in all animal species. The average Cl, V _ss and t _1/2 were 0.065 L/h, 0.019 L and 28.7 min in mice, 0.47 ± 0.06 L/h, 0.117 ± 0.029 L and 29.7 ± 12.2 min in rats, 2.77 ± 0.88 L/h, 1.83 ± 0.60 L and 84.4 ± 16.9 min in rabbits and 14.0 ± 0.7 L/h, 9.2 ± 10.1 L and 54.5 ± 57.2 min in dogs, respectively. Based on animal data, human pharmacokinetic parameters of Cl, V _ss and t _1/2 were predicted by simple allometry. In addition, actual concentration-time profiles obtained from animals were transformed to human profiles by species-invariant times of kallynochron, apolysichron and dienetichron. The predicted human pharmacokinetic parameters of Cl, V _ss and t _1/2 by using simple allometry and species-invariant time transformation method ranged from 48.3–97.2 L/h, 49.1–92.9 L and 45.6–187.2 min, respectively. Those predicted parameters of oleanolic acid may be useful in designing dosing schedules of oleanolic acid in future clinical studies. Authors contributed equally to this work.     

Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50 mg/kg for oral administration), rats (5, 10 and 20 mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (V(ss)) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were ClxMLP=49.8 W(0.861), Cl=5.20 W(0.523) and V(ss)=4.46 W(0.764). Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data. Copyright (c) 2005 John Wiley & Sons, Ltd.     

栀灯注射液中栀子苷、灯盏花素的大鼠药代动力学初步研究

目的建立大鼠血浆样品中栀子苷和灯盏花素的高效液相色谱检测方法,并研究栀灯注射液在大鼠体内的药代动力学特征,为其剂量设置提供依据。方法大鼠尾静脉注射栀灯注射液高、中、低3个剂量后检测不同时间血浆中栀子苷和灯盏花素的浓度,并估算药代动力学参数。结果所建立的测定方法对灯盏花素的线性范围为0.2~40μg/mL,对栀子苷的线性范围为0.5~200μg/mL,回收率大于85%,日内及日间RSD均小于10%。静注给予栀灯注射液后,灯盏花素和栀子苷的平均消除半衰期分别为21.6和72.6 min,分布容积分别为0.23~1.24和0.37~1.05 L/kg。结论建立的大鼠血浆中灯盏花素和栀子苷HPLC测定方法适合于药代动力学研究。     

灯盏花素阳离子脂质体的制备

目的：制备灯盏花素阳离子脂质体和普通脂质体并对其相关性质进行考察。方法：采用薄膜分散法制备灯盏花素脂质体;以包封率为指标,通过正交试验对处方进行优化。考察灯盏花素普通脂质体和阳离子脂质体的体外释放行为。结果：制备的灯盏花素阳离子脂质体性质稳定,包封率为（76.42±1.973）%,平均粒径为（186±35） nm,Zeta电位为（48.9±9.83） mV。灯盏花素普通脂质体和阳离子脂质体的释放过程的拟合方程分别为lnln［1/(1-Q)］=0.779 7lnt-2.318 7(r=0.973 9)和lnln［1/(1-Q)］=0.355 3lnt-3.197(r=0.989 9)。结论：确定了最优处方,制备得到包封率较高且状态稳定的灯盏花素阳离子脂质体。     

紫杉醇纳米脂质体的制备与大鼠体内药动学

目的:制备紫杉醇新型纳米脂质体并研究其在大鼠体内的药动学。方法:采用薄膜分散超声结合冷冻干燥制备紫杉醇纳米脂质体。大鼠尾静脉注射紫杉醇脂质体及市售紫杉醇注射液Anzatax,血浆样品经乙醚提取后用反相高效液相色谱法(RP-HPLC)检测血浆紫杉醇浓度,并用3P87软件包估算药动学参数。色谱条件如下:色谱柱为Gemini ODS(150 mm×4.6 mm,5μm),流动相为0．035mol·L-1乙酸铵缓冲液(pH 5．0)-乙腈(45:50),流速1．0 mL·min,检测波长230 nm,地西泮为内标。结果:制备的紫杉醇纳米脂质体的体积权重粒径为(54.1±26．0)nm,包封率大于80％,符合药典规定,且24 h内与葡萄糖注射液配伍稳定。紫杉醇脂质体及市售紫杉醇注射液Anzatax经大鼠尾静脉注射后均符合二室模型,脂质体组的消除半衰期(t1/2β)显著长于Anzatax组[(3．38±0．39)vs．(2．49±0．63)h,P<0．05];其他药动学参数经方差分析均无显著性差异。紫杉醇脂质体与Anzatax的AUC0-8h比值为88．13％。结论:制备的紫杉醇纳米脂质体在大鼠体内的药动物参数与市售紫杉醇注射液Anzatax比较,t1/2β稍有延长,AUC0-8h值相近。     

Biliary excretion of manganese in rats, rabbits, and dogs

The disappearance of ⁵⁴Mn from the blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.3, 1.0, 3.0, and 10 mg/kg of manganese. The maximal rate of excretion of manganese into the bile was approximately 8.5 μg/min/kg after the 2 higher doses. The bile concentration was found to be 100–200 times that in the plasma for the 3 lower doses. This was due both to the higher concentration of manganese in the liver than the plasma (15- to 20-fold) and in the bile than the liver (6- to 10-fold). Bile had about 50% the affinity for manganese as plasma, and about 20% the affinity as did liver. This suggests that manganese does not pass from plasma to bile because of a higher affinity for bile than plasma. These results show that manganese is excreted into the bile of rats against an apparent concentration gradient and suggest that an active transport mechanism for the excretion of manganese may exist. Lead does not decrease the excretion of manganese, and the excretion of manganese is not highly temperature-dependent as is that of lead, suggesting that manganese is excreted by a different pathway than lead. Manganese is also excreted into the bile of rabbits and dogs with a species variation in the rate of excretion. Manganese did not decrease bile flow in rats when it was given alone or when bilirubin was given 15 min before manganese administration; however, a marked decrease in flow was observed when bilirubin was given 15 min after manganese administration.     

Biliary excretion of arsenic in rats,rabbits, and dogs

The disappearance of ⁷⁴As from blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.01, 0.46, 1.0, 2.1, and 4.6 mg/kg of arsenic given as the trichloride. Arsenic disappearance from plasma was biphasic; the half-life during the late phase was greater than 2 hr. Even though the arsenic was injected iv, the concentration in the blood increased through the first 2 hr. Arsenic was rapidly excreted into the bile, reaching its highest rate of excretion 6 min after administration, after which it rapidly decreased. This rapid decrease in excretion is due to redistribution of arsenic from the liver to the blood. Arsenic enters bile against an apparent bile/plasma concentration gradient of 630, 8 min after 1 mg/kg of arsenic. At this time the liver/plasma gradient is 17 and the liver/bile gradient is 37. Twenty-five percent of the arsenic administered to bile duct-cannulated rats is excreted into the bile within 2 hr. However, less than 10% of the administered dose is excreted into the feces of intact rats over a 7-day period. In the rabbit and dog, arsenic is excreted into the bile at a much slower rate. These data demonstrate that arsenic is excreted into the bile, and this occurs against a large bile/plasma concentration gradient in rats, suggesting excretion by an active transport mechanism. However, the overall importance of bile as a route of elimination for arsenic is minimized due to enterohepatic circulation and species variations in its biliary excretion rate.     

Biliary excretion of lead in rats rabbits,and dogs

The disappearance of ²¹⁰Pb from the blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.1, 0.3, 1.0, 3.0, or 10 mg/kg of inorganic lead. The maximal rate of excretion of lead into the bile was approximately 1.0 μg/min/kg after the 3 higher doses. The concentration of lead in the bile was found to be 40–100 times that in the plasma for the 3 lower doses. This was due largely to the higher concentration of lead in the liver than in the plasma (10- to 35-fold higher) and partially to the higher concentration in the bile than in the liver (3- to 4-fold higher). Essentially none of the lead in the bile, plasma, and liver was dialyzable. Lead exhibited a 5-fold greater affinity for liver than bile and a 3-fold greater affinity for liver than plasma. The mitochondrial fraction contained the highest concentration of lead. Changing the rectal temperature of rats altered the biliary excretion of lead markedly; when the temperature was increased from 30 to 40°C, the biliary excretion of lead increased 20-fold. Marked species differences in the biliary excretion of lead were observed. Rabbits excreted lead into the bile at a rate less than one-half, and dogs excreted lead at a rate less than one-fiftieth, that observed in the rat. The results indicate that lead is excreted into the bile of rats against an apparent concentration gradient and that an apparent transport maximum exists. This suggests that the liver may have an active transport mechanism for the excretion of metals.     

The pharmacokinetics of indecainide in mice, rats, dogs, and monkeys

The pharmacokinetics of indecainide, a new antiarrhythmic agent, were studied in mice, rats, dogs, and monkeys. The drug was well absorbed in all species tested resulting in peak plasma levels of drug within 2 hr. The plasma half-life of indecainide after acute oral administration was 3-5 hr in rats, dogs, and monkeys but considerably shorter in mice. The plasma half-life of indecainide was dose-dependent in dogs and increased slightly with chronic dosing. Peak plasma levels of drug were also dose-dependent in dogs and monkeys. Fecal elimination was the primary route of excretion of the drug in rats and mice after oral dosing. Fifty per cent of the dose was excreted in the bile of rats which was then subject to enterohepatic circulation. Urinary elimination was the predominant excretory route in the dog. Tissue distribution of radioactivity in rats showed that tissues which first encounter the drug have the highest levels of radioactivity. The highest concentrations were found in the stomach, intestine, liver, and kidney, whereas very low levels were observed in the fat and brain. Except for liver and kidney, only very low levels were present after 24 hr.     

Interspecies pharmacokinetic scaling of a new carbapenem,DA-1131, in mice,rats, rabbits and dogs,and prediction of human pharmacokinetics

The total body clearance (Cl), renal clearance (Cl_r), and apparent volume of distribution at steady state (V_ss) of DA-1131, a new carbapenem, after intravenous (iv) administration of the drug, 50 mg kg⁻¹, to mice, rats, rabbits, and dogs were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict these parameters in humans. Significant linear relationships were obtained between log[Cl (L h⁻¹)] and log[W (kg)] (r = 0.995; p = 0.00503), log[Cl_r (L h⁻¹)] and log[W (kg)] (r = 0.998; p = 0.0429), and log[V_ss (L)] and log[W (kg)] (r = 0.987; p = 0.0126). The corresponding allometric equations were Cl = 0.706W^0.811, Cl_r = 0.318W^0.888, and V_ss = 0.194W^0.981. These allometric equations were extrapolated to predict the Cl and V_ss for DA-1131 in humans based on 70 kg body weight. The Cl and V_ss for humans predicted from the four animal data well fitted to regression lines of animal data. Interspecies scale-up of plasma concentration–time data for the four species using a complex Dedrick plot resulted in similar profiles. In addition, the concentration in plasma–time profile predicted using the four animal data well fitted to a complex Dedrick plot of animal data. Our results indicate that the DA-1131 data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies. © 1998 John Wiley & Sons, Ltd.     

Interspecies pharmacokinetic scaling of DA-8159, a new erectogenic, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

Time-averaged total body clearance (Cl) and apparent volume of distribution at steady state (V(SS)) of DA-8159 after intravenous administration to mice (30 mg/kg), rats (30 mg/kg), rabbits (30 mg/kg) and dogs (3 mg/kg) were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict those in humans. Significant linear relationships were obtained between log Cl (l/h) and log W (kg) (r = 0.992; p = 0.0079) and log V(SS) (l) and log W (kg) (r = 0.999; p < 0.0001). The corresponding allometric equations were Cl = 4.36 W(0.492) and V(SS) = 6.41 W(0.911). These allometric equations were extrapolated to predict the Cl and V(SS) for DA-8159 in humans based on the 70 kg body weights. In addition, concentrations in the plasma-time profile predicted using the four animal data fitted to a complex Dedrick plot of animal data. Our results indicated that the DA-8159 data obtained from four laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.     

辣椒碱多囊脂质体的制备及在大鼠体内的药动学研究

目的 制备辣椒碱多囊脂质体,并考察其包封率和在大鼠体内的药动学.方法采用复乳法制备辣椒碱多囊脂质体、单因素筛选处方,并考察大鼠sc辣椒碱多囊脂质体后的体内药动学.结果制备的辣椒碱多囊脂质体的外观圆整,大小均匀,包封率为71.9%±3.8%,平均粒径为8.1 μm.大鼠sc辣椒碱多囊脂质体后,与辣椒碱溶液相比,Cmax分...     

Comparative pharmacokinetics of a new benzamide neuroleptic drug in rats, dogs and monkeys using a stable isotope technique

Comparative pharmacokinetics of a new benzamide neuroleptic drug, cis-N-(1-benzyl-2-methylpyrrolidine-3-yl)-5-chloro-2-methoxy-4-met hylamino benzamide (NBND) was studied in rats, dogs and monkeys using two deuterium-labelled compounds. NBND and 2H3-NBND, which showed no biological isotope effect, were co-administered p.o. and i.v. to rats, dogs and monkeys, and the plasma concentrations of unchanged drugs were simultaneously determined by g.l.c.-chemical ionization mass spectrometry with 2H7-NBND as an internal standard. The plasma half-lives (t1/2 beta) after i.v. administration were 1.6, 4.7 and 2.2 h in rats, dogs and monkeys at a dose of 0.2 mg/kg. Plasma clearances were 4.3, 1.7 and 1.4 l/h per kg in rats, dogs and monkeys. Absorption rate constants (Kab) were 1.1, 0.58 and 0.54 per h in rats, dogs and monkeys, at doses of 10, 3 and 5 mg/kg, respectively. Absolute bioavailabilities were 0.8, 9.5 and 1.3% in rats, dogs and monkeys, suggesting that all these species showed large first-pass effects, probably due to hepatic metabolism.     

芍药甙在兔和大鼠体内的药动学研究

兔iv25mg·kg~(-1)芍药甙后,血药浓度—时间曲线符合二室模型。药动学参数为T_(1/2α)=5.93min,T_(1/2β)66.02min,V(?)=516.8ml·kg~(-1),CL=6.11ml·kg~(-1)·min~(-1)。兔ig250mg·kg~(-1)芍药甙,生物利用度为F=7.24％±4.15％,T_(max)=77.4min,C_(max)=21.57mg·L~(-1)大鼠ig550mg·kg~(-1)芍药甙,24h内粪、尿排泄量及iv55mg·kg~(-1)7h内胆汁排泄量分别占给药量的10.61％、1.08％、864％。离体肝脏灌流结果提示:芍药甙在肝内代谢少.