Advances in Clinical Pharmacokinetics of Herbal Medicines

Herbs have been used for treating various ailments since medicine began. The belief that natural products are much safer than synthetic drugs has led to dramatic growth of herbal medicine usage. Like synthetic drugs, herbal preparations also have potential to cause adverse effects and drug interactions. Knowledge of herbal pharmacokinetics is needed to explain and predict various events related to the efficacy and toxicity of herbal preparations. However, Pharmacokinetics and drug interactions of herbal preparation have not been yet systematically studied. Especially, the clinical phannacokinetic studies on herbal preparations are limited to some widely used herbs such as St.John＇s Wort and Gingko biloba. In this review, clinical pharmacokinetics studies that have been conducted for herbal medicine products since 2001 are evaluated. Scientifically controlled clinical studies on various herb-drug interactions are also discussed.     

Pharmacokinetics of clonazepam in developing rats.

Time-concentration studies of clonazepam (CZP) were performed in 7-, 14-, and 28-day-old Sprague-Dawley rats. Blood samples and brains were collected at specific intervals following a single subcutaneous (SC) injection of 2.5 mg/kg of CZP. CZP concentrations were measured both in plasma and brain samples by high performance liquid chromatography. Pharmacokinetic parameters were calculated using R-Strip for each age group. The results were compared between the age groups and with those of a similar study in our laboratory using lower dose CZP (1 mg/kg) SC injections in adult Sprague-Dawley rats. Younger rats had slower, delayed and higher peak concentrations, larger areas under the curve (AUC), longer elimination half lives (T1/2), smaller volumes of distribution (Vd) and slower clearances (C1). 28-day-old rats showed the fastest C1, smallest AUC and largest Vd. These data suggest that the pharmacokinetic behavior of CZP is age-dependent. If this is true in human, it is implicated in dosing of neonatal or pediatric patients.

     

Pharmacokinetics of Aminoglycosides

The Pharmacokinetics informations of aminoglycosides, their monograph and clinical Pharmacokinetics parameters are reported in this review. The Aminoglycosides are highly polarity and in reserve for serious infections caused by aerobic gram-negative bacteria and some gram-positive bacteria but their toxicity are major limitations in clinical use.     

Study on the Pharmacokinetics of Berberine in Rabbits

用ＲＰＨＰＬＣ方法研究了给家兔灌胃黄连素的吸收情况及药代动力学。结果表明，给家兔灌胃黄连素５０ｍｇ／ｋｇ，其血药浓度时间数据用３Ｐ８７药代动力学程序软件处理，经自动拟合，黄连素给家兔灌胃后的药代动力学模型符合一室开放模型，其主要药代动力学参数Ｔ（ｐｅａｋ）为（０６２±０２５）ｈ，Ｃ（ｍａｘ）为（９２７２±５０８９）μｇ／Ｌ，曲线下的面积ＡＵＣ值为（４９１７±２９５５）μｇ·ｈ／Ｌ。此结果表明，家兔口服黄连素后能被迅速吸收，且达到了有效的血药浓度     

Ultrastructural features of gentamicin-induced glomerular damages in rabbits

In order to clarify whether gentamicin (GM) could damage the renal glomeruli,theultrastructural changes of the renal cortex were observed in rabbits after they received a singleinjection of 100 mg/kg GM or 100 mg·kg~(-10)·d~(-1) GM for 3 consecutive days.The animals ofthe control group received equal amount of normal saline.It was found that some myelin figuresappeared in the epithelial cells of the proximal tubules as early as 1 h after a single GM injec-tion;severe swelling,degeneration,and obvious changes of the organelles were seen in the en-dothelial cells of the glomerular capillaries,the podocytes and the epithelial cells of the proxi-mal tubules 24 h after an injection of GM;and fusion of the processes of podocytes,thickeningof the glomerular membrane and necrosis of the epithelial cells of a part of the'proximal tubuleswere encountered 24h after the 3rd GM injection.These findings demonstrate that GM can in-jure not only the proximal tubules but also the glomeruli in rabbits.     

An experimental study of pituitary transplantations in rabbits.

Experimental pituitary transplantations were carried out between the New Zealand white and American chinchilla rabbits. These two kinds of experimental rabbits were of different genotypes. The grafts were transplanted underneath the median eminences of the recipients after hypophysectomy. The rabbits with the transplants were treated with cyclosporine (CsA) and prednisone for the first month. Blood samples were taken at regular intervals for the determinations of serum thyroxine, prolactin and luteinizing hormone. The results suggested that neonatal grafts could survive and function almost normally with the aid of CsA and prednisone, but not without them. The results also disclosed that the interrelationship between the pituitary graft and the host's hypothalamus could be established. Pituitary transplantation from adult rabbit donors failed even though the recipients had been treated with CsA and prednisone in our experiment.

     

Influence of insulin treatment on hyperproteolysis of skeletal muscle in scald sepsis in rabbits

Objective To study the regulative effects of intensive insulin treatment on hyperproteolysis of skeletal musle in burn sepsis in rabbits. Methods Male white rabbits were injured with boiling water and endotoxin （2 mg/kg） to establish scald and sepsis model. The plasma glucose level in physiologicrange was controlled with insulin and the proteolytic rate and the expression of proteasome in extensor digitorium longus were determined.     

Pharmacokinetics of piroxicam-β-cyclodextrin inclusion complexes in Beagle dogs

目的 研究吡罗昔康环糊精包合物Beagle犬体内药物动力学.方法 6只Beagle犬采用随机、双周期交叉给药,单剂量灌胃给予吡罗昔康受试制剂或参比制剂,用HPLC法测定吡罗昔康血浆浓度,用统计矩原理进行血药浓度-时间数据分析.结果 吡罗昔康包合物的达峰时间tmax快于普通片剂,分别为(0.89 ±0.09)、(3.92±0.49)h,两者有显著差异(P＜0.01),两者的半衰期t1/2分别为(31.30±4.38)、(29.38±1.83)h,曲线下面积(AUC0～1)分别为(242.92±30.04)、(230.55±8.06)μg(h·ml),最高血药浓度(Cmax)分别为(7.82±0.44)、(7.49±0.36)μg/ml,清除率(Cl)分别为(80.92±10.65)、(85.27±2.95)ml/h,表观分部容积(Vd)分别为(3.36±0.51)、(3.22±0.19)L,均无明显差异(P＞0.05),吡罗昔康包合物相对于市售片剂的相对生物利用度为106.74％.结论 建立的HPLC分析方法准确可靠.两种剂型的生物利用度相似,将吡罗昔康制成包合物后能大大加快药物在体内的吸收速度,使其更快发挥药效.     

Study of stereoselective pharmacokinetics of anisodamine enantiomers in rabbits by capillary electrophoresis

The purpose of this study was to determine the pharmacokinetics of anisodamine enantiomers in plasma after oral and intravenous administration of racemic anisodamine in rabbits. A capillary electrophoresis method for the simultaneous separation of two pairs ofenantiomers in plasma has been firstly developed and validated. Usinga 75 mM phosphate buffer containing 25 mM carhoxymethylated-gamma cyclodextrin at pH 2.5,     

家兔血清中二氯乙酸钠浓度的测定

目的：建立用反相离子对色谱法测定家兔血清中游离二氯乙酸钠（ Ｄ Ｃ Ａ Ｎａ）浓度的方法。方法：用高效液相色谱法测定了家兔血清中 Ｄ Ｃ Ａ Ｎａ 的含量。 Ｄ Ｃ Ａ Ｎａ 在碱性条件下与水合肼定量生成稳定的腙,以 Ｉ Ｐ Ｒ Ｂ８为色谱试剂,在 Ｚｏｒｂａｓ Ｏ Ｄ Ｓ（４８ ｍ ｍ ×２５０ ｍ ｍ ）柱上,以水 甲醇 Ｉ Ｒ Ｐ Ｂ８为流动相进行人离。结果：分离灵敏度为００５ Ａ Ｕ Ｆ Ｓ,在２６８ ｎｍ 处,衍生物线性范围０６５～５００μｇ／ｍ ｌ,ｒ＝ ０９９９５,回收率（９８５±３３）％ 。结论：此方法为研究 Ｄ Ｃ Ａ Ｎａ 在人体内的药代动力学及药效学提供了参考。     

双氯芬酸钠微乳的家兔体内药代动力学考察

目的 :考察双氯芬酸钠微乳在家兔体内的药代动力学过程。方法 :家兔单次口服双氯芬酸钠微乳和双氯芬酸钠混悬液后 ,用 HPL C法测定血中双氯芬酸钠浓度。 结果 :双氯芬酸钠微乳和混悬液的 AU C0 -∞ 分别为 13.45 6和 10 .5 84μg· h· m l- 1 ,cmax 1 为 2 .85 2和 3.145 μg/m l,tmax1 为 1.438和 0 .75 0 h。 结论 :双氯芬酸钠微乳在家兔体内吸收过程较为平缓 ,可在较长时间内维持一定的血药浓度。     

二氯乙酸钠药物动力学的统计矩分析

二氯乙酸钠（ＤＣＡ－Ｎａ）为乳酸脱氢酶激活剂，用于代谢性乳酸酸中毒的治疗，作者用反相离子对高效液相色谱法检测血清中ＤＣＡ－Ｎａ的浓度，并用统计矩法分析ＤＣＡ－Ｎａ在兔体内的药物动力学。提示：随着剂量的增加，ＤＣＡ－Ｎａ在兔体内可能存在非线性药物动力学，并在某些器官组织中明显浓集。     

氢溴酸右美沙芬滴鼻液人体药代动力学研究

采用高效液相色谱-荧光法测定氢溴酸右美沙芬血药浓度,研究了8名健康志愿者随机交叉单剂量给予滴鼻液7.5mg滴鼻或片剂60mg口服的药代动力学。结果表明,两种剂型经不同途径给药的药物体内过程符合线性二房室模型特征。小剂量滴鼻液经鼻腔粘膜吸收,因其避免了肝脏的代谢,故与口服片剂比较,具有相对吸收迅速,生物利用度较高的药代动力学特点。提示该滴鼻液系一符合临床应用要求的镇咳新剂型。     

紫外分光光度法测定兔血清中二氯乙酸钠浓度

作建立检测二氯乙酸钠血清浓度的紫外分光光度法，平均回收率为１０１．４％，日内变异为３．３％，日间变异为３．８％，最低检测浓度为１ｍｇ／Ｌ。应用本法研究二氯乙酸钠（ｉｖ，１８０ｍｇ／ｋｇ）在兔体内的药代动力学，主要药代动力学参数为：Ｔ１／２＝０．６７ｈ，Ｖｄ＝０．２８Ｌ／ｋｇ，Ｋ＝１．１ｈ＾－１，Ｃｌ＝０．３１Ｌ／ｋｇ／ｈ，ＡＵＣ＝６０５．１ｍｇ．ｈ／Ｌ。     

甲基黄酮醇胺在家兔体内的代谢动力学

建立了兔血清中甲基黄酮醇胺的高效薄层荧光扫描检测方法，血清中甲基黄酮醇胺的线性检测范围为０．１～４ｍｇ／Ｌ，最低检出浓度为０．０４ｍｇ／Ｌ；研究了甲基黄酮醇胺在家兔体内的代谢动力学，甲基黄酮醇胺在家兔体内的代谢动力学符合二室开放模型，分布相半衰期为０．２６±０．１１ｈ，消除相半衰期为４．０９±１．２０ｈ。     

高效液相色谱法测定家兔血浆中安妥沙星浓度及药代动力学参数

目的:建立测定家兔血浆中安妥沙星浓度的高效液相色谱方法,探讨安妥沙星在家兔体内的药代动力学特征。方法:取安妥沙星片,按25 mg/kg剂量,研细,分散于0.5%羧甲基纤维素钠溶液中,给家兔灌胃,采血,血样经高氯酸处理后进行高效液相色谱法分析。色谱柱条件:Phenomenex C₁₈柱(250 mm×4.6 mm,4μm);乙腈:50 mmol/L枸橼酸溶液:1 mol/L醋酸胺溶液(19:80:1,体积比)为流动相,流速1.0ml/min;检测波长为295nm,柱温40℃。结果:安妥沙星在家兔血浆中的线性范围为0.164~10.5μg/ml,最低定量限为0.164μg/ml。日内及日间变异均<10%,准确度相对误差<5%。血浆中回收率>80%。实验条件下安妥沙星在家兔体内的药代动力学参数:血药浓度时间曲线下面积为(46.17±13.99)mg·L-1·h-1,达峰时间为(0.9±0.14)h,峰浓度为(5.15±0.54)mg/L,生物半衰期为(11.98±4.02)h,清除率为(0.58±0.19)L·kg-1·h-1。结论:该方法经考察符合生物样品的测定要求,可用于测定家兔血浆安妥沙星浓度和药代动力学的研究。     

氟氧头孢在家兔体内的药代动力学和组织分布研究

目的：研究氟氧头孢在家兔体内的药代动力学和组织分布。方法：家兔单剂量静脉推注５０ ｍ ｇ／ｋｇ 氟氧头孢,采用ＨＰＬＣ法测定体液及组织中药物浓度。结果：静脉给药后血浆药－时曲线符合二室开放模型,氟氧头孢体内分布迅速,分布半衰期仅为０．０２３ ｈ,消除半衰期为０．２１３ ｈ, ＡＵＣ为（７９．９４±１３．３１） ｈ·μｇ／ｍ ｌ, 尿液、胆汁、肺、肾脏、卵巢及子宫中药物浓度较高。结论：氟氧头孢是一体内分布广、组织浓度高、消除半衰期短的头孢类抗生素     

环磷酰胺对丁硫氨酸亚砜胺在大鼠体内的药代动力学影响

目的研究环磷酰胺 (CTX)对丁硫氨酸亚砜胺 (BSO)在SD大鼠体内的药代动力学的影响。　方法SD大鼠腹腔注射CTX 2 0mg/kg(用药组 )或生理盐水 (对照组 ) 4d后 ,静脉注射BSO 2 0 0mg/kg。以邻 -苯二甲醛(OPA)柱前衍生反相HPLC为检测手段 ,测定血浆中BSO的浓度。以 3P87软件对实验数据进行拟合 ,判断房室模型并计算药代动力学参数。　结果SD大鼠静脉注射BSO 2 0 0mg/kg ,体内的动力学过程为二室模型 ,T1/2α为 2 7.4±5 .3min ,T1/2 β为 15 9.3± 10 7.3min ,CLs 为 11.8± 2 .3ml·min-1·kg-1,AUC为 2 99.36± 5 0 .13μg·ml-1·h ;SD大鼠在用CTX后 ,BSO在其体内动力学特征也是二室模型 ,T1/2α为 2 5 .2± 2 .2min ,T1/2 β为 114 .3± 2 5 .9min ,CLs 为 13.8± 3.8ml·min-1·kg-1,AUC为 2 5 6 .5 5± 6 6 .2 8μg·ml-1·h。用药组和对照组的药代动力学参数无显著性差异。结论CTX不影响BSO在大鼠体内的药代动力学过程。