灯盏花素在小鼠体内药物动力学研究

目的:研究灯盏花素在小鼠体内的药物动力学和绝对生物利用度。方法:采用固相萃取 高效液相色谱(SPE HPLC)法,测定小鼠静脉注射灯盏花素5 0mg·kg-1和灌胃15 0mg·kg-1后血浆灯盏乙素浓度,3p97程序处理数据。结果:小鼠静注灯盏花素后灯盏乙素的血浓 时间变化符合三房室模型,AUC、C0 和T1 2 β分别为12 .97±3.5 5mg·L-1·h、132 .2 3±39.90mg·L-1和4 .0 4±1.2 9h。灌胃后药物吸收很快,但血浓低。采用非房室模型法计算AUC为1.97±0 .5 3mg·L-1·h ,T1 2Ke 为3.4 1±1.2 3h。绝对生物利用度为5 .0 5 %。结论:灯盏花素经静注在小鼠体内的药代动力学符合三室模型。灌胃给药吸收快,但吸收差,绝对生物利用度低,且药时曲线变化不规则。     

灯盏花素缓释片在Beagle犬体内相对生物利用度的研究

目的　探讨灯盏花素缓释片在动物体内的药物动力学规律 ,并进行相对生物利用度研究。方法　采用双周期交叉试验设计 ,对Beagle犬单剂量顿服灯盏花素缓释片和参比制剂的动力学参数进行比较。结果　采用尿药法进行数据处理 ,参比制剂与供试制剂的尿药总排泄量 (Xu)分别为 375 92 5± 4 7 2 3μg和 394 5 92± 32 84 μg ;生物半衰期 (t1/2 )分别为 7 197± 0 5 91h和 12 6 2± 1 2 0 7h。结论　以吸收总量为指标 ,灯盏花素缓释片与参比制剂相比是生物等效制剂 ,并具有缓释特征。     

HPLC法测定灯盏花素片中灯盏花乙素的含量

目的:建立灯盏花素片中灯盏花乙素的含量测定方法;方法:采用高效液相色谱法,使用C18柱,流动相为甲醇-水-冰醋酸(30:70:1),检测波长335nm;结果:该制剂中灯盏花乙素在0.2～4.0μg范围内线性良好,平均回收率为100.21%,RSD为1.48%;结论:该方法简便、快速、准确,可用于灯盏花素片的含量测定和质量控制.     

HPLC法测定灯盏花素片中灯盏花乙素的含量

目的建立灯盏花素片中灯盏花乙素的含量测定方法。方法采用高效液相色谱法,使用C18柱,流动相为甲醇-水-冰醋酸(30∶70∶1),检测波长335nm。结果该制剂中灯盏花乙素在0.0624～0.312μg范围内线性良好,平均回收率为99.92%,RSD为0.24%。结论该方法简便、快速、准确,可用于灯盏花素片的含量测定和质量控制。     

灯盏花素分散片在健康人体内的相对生物利用度研究

目的研究灯盏花素分散片与灯盏花素片在健康男性志愿者体内的相对生物利用度。方法采用随机双周期自身交叉对照试验设计,18名健康男性受试者分别经口给予受试制剂灯盏花素分散片和参比制剂灯盏花素片80 mg,采用LC-MS-MS法测定给药后不同时间异灯盏乙素的血药质量浓度。利用DAS软件计算药动学参数和进行统计分析,通过方差分析和双单侧t检验及90%置信区间法进行生物利用度评价。结果受试制剂与参比制剂中异灯盏乙素的ρmax为(75.81±23.24)、(62.17±17.82)μg.L-1,tmax为(6.50±1.34)、(7.78±1.52)h,AUC0→t为(454.1±194.7)、(403.9±133.3)μg.h.L-1,AUC0→∞为(460.1±199.8)、(410.3±137.1)μg.h.L-1。结论受试制剂ρmax比参比制剂大,疗效更高;受试制剂tmax比参比制剂小,起效更快;受试制剂对参比制剂的相对生物利用度(F,以AUC0-∞作为评价依据)为(116.5±43.5)%,灯盏花素分散片生物利用度较普通片高。     

灯盏花素口服微乳的制备

目的制备灯盏花素口服微乳并建立其包裹率测定方法。方法采用单因素法及伪三元相图法优选处方,葡聚糖凝胶柱层析法分离含药微乳与游离药物,以纯化水为洗脱液,高效液相色谱法测定药物含量。结果优选的油相、表面活性剂及助表面活性剂分别为油酸乙酯、聚山梨酯80及聚乙二醇400。柱层析分离方法药物回收率100.37%,加样回收率97.9%,药物含量测定方法回收率99.94%,线性范围12～360 μg• mL－1。样品包封率（93.2±1.0）%。结论所建立的方法可用于制备灯盏花素口服微乳并测定其包裹率。     

灯盏花素的研究进展

灯盏花素及其制剂在心脑血管疾病治疗领域展现了良好的疗效,本文综述了近年来灯盏花素在药理学、药动学、制剂、制备、结构改造及临床应用等方面的最新研究进展。     

灯盏花素缓释片在兔体内的绝对生物利用度

目的测定兔静注灯盏花素注射剂25 mg及兔口服灯盏花素缓释片120 mg后血浆中野黄芩苷的浓度,研究2种制剂的药动学参数和缓释片的绝对生物利用度。方法采用C_8固相萃取法预处理血浆样品,兔静注和口服灯盏花素后的血药浓度分别采用高效液相色谱-紫外检测法和高效液相色谱-质谱检测法测定。结果兔静注灯盏花素注射剂后的药-时曲线符合三室模型。兔口服灯盏花素缓释片后的药-时曲线难以用现有的房室模型拟合,6只兔的药-时曲线及药动学参数差异较大。经剂量校正,口服给药的绝对生物利用度F为(0.18±0.15)%。结论兔口服灯盏花素缓释片后的绝对生物利用度很低。     

灯盏花素分散片的制剂工艺研究

目的 考察处方中组分对灯盏花素分散片制剂的影响。方法 以崩解时限为指标,采用正交设计试验,对灯盏花素分散片处方进行筛选。结果 按优化处方制备的灯盏花素分散片．可在3分钟内完全崩解。结论 优化处方的灯盏花素分散片其体外溶出度明显优于普通片。     

灯盏花素-β-环糊精包合物片剂的制备工艺研究

目的研究灯盏花素-β-环糊精包合物片剂的最佳工艺。方法采用正交试验设计法,以0.5,5,30 min溶出百分率为考察指标选择最佳工艺。结果优选工艺为交联羧甲基纤维素钠10%,微晶纤维素25%,甘露醇30%。结论所用方法制备灯盏花素β-环糊精包合物片剂合理、可行。     

Triglyceride-mimetic prodrugs of scutellarin enhance oral bioavailability by promoting intestinal lymphatic transport and avoiding first-pass metabolism

The intestinal capillary pathway is the most common way to absorb oral drugs, but for drugs with poor solubility and permeability and high first-pass metabolism, this pathway is very inefficient. Although intestinal lymphatic transport of lipophilic drugs or prodrugs is a promising strategy to improve the oral delivery efficiency of these drugs. The prodrug strategy for modifying compounds with Log P > 5 to promote intestinal lymphatic transport is a common approach. However, transport of poor liposoluble compounds (Log P < 0) through intestinal lymph has not been reported. Herein, triglyceride-mimetic prodrugs of scutellarin were designed and synthesized to promote intestinal lymphatic transport and increase oral bioavailability. Lymphatic transport and pharmacokinetic experiments showed that two prodrugs did promote intestinal lymphatic transport of scutellarin and the relative oral bioavailability was 2.24- and 2.45-fold of scutellarin, respectively. In summary, triglyceride-mimetic prodrugs strategy was used for the first time to study intestinal lymphatic transport of scutellarin with Log P < 0, which could further broaden the application range of drugs to improve oral bioavailability with the assistance of intestinal lymphatic transport.     

Intestinal lymphatic absorption of cyclosporin a following oral administration in an olive oil solution in rats

The intestinal lymphatic absorption of cyclosporin A (CyA) following oral adminstration of 6·5 0·6 and 25·2±1·4mg kg^?1 doses of the drug dissolved in an olive oil solution was studied using a thoracic duct-cannulated rat model. Cumulative lymph samples were collected for up to 114h post-dosing and assayed by liquid scintillation counting. In this study, the estimated amount of lymphatically absorbed CyA was 0·35±0·13 and 0·47±0·29 per cent of the respective doses. In terms of the overall oral bioavailability of CyA (F_po) by all absorptive mechanisms, the intestinal lymphatics accounted for the absorption of approximately 2 per cent of the total amount of absorbed drug. F_po was 21·3±2·5 per cent. The results of this study suggested that lipophilicity alone was not the only factor governing intestinal lymphatic drug absorption. An explanation for the low level of lymphatic CyA absorption is presented. In addition, some reasons for the low overall oral bioavailability of CyA are discussed.     

Structured triglyceride vehicles for oral delivery of halofantrine: examination of intestinal lymphatic transport and bioavailability in conscious rats

Purpose. To compare the influence of triglyceride vehicle intramolecular structure on the intestinal lymphatic transport and systemic absorption of halofantrine in conscious rats. Methods. Conscious, lymph cannulated and nonlymph cannulated rats were dosed orally with three structurally different triglycerides; sunflower oil, and two structured triglycerides containing different proportion and position of medium-(M) and long-chain (L) fatty acids on the glycerol backbone. The two structured triglycerides were abbreviated MLM and LML to reflect the structural position on the glycerol. The concentration of halofantrine in blood and lymph samples was analyzed by HPLC. Results. Both the lymphatic transport and the total absorption of halofantrine were enhanced by the use the MLM triglyceride. The estimated total absorption of halofantrine in the lymph cannulated animals was higher than in the nonlymph cannulated animals, and this was most pronounced for the animals dosed with the structured triglycerides. Conclusions. Using MLM as vehicle increases the portal absorption of halofantrine and results in similar lymphatic transport levels when compared to sunflower oil. Total absorption when assessed as absorption in the blood plus lymphatic transport for halofantrine after administration in the MLM triglyceride was higher than after administration in sunflower oil.     

Bioavailability of lycopene in the rat: the role of intestinal lymphatic transport

Objectives As a natural antioxidant derived from dietary sources, lycopene has attracted considerable attention as a potent chemopreventative agent. Lycopene is an extremely lipophilic compound and absorption from dietary sources is estimated to be low and highly variable. As a result, plasma lycopene concentrations are poorly correlated with dietary intake of lycopene rich food stuffs. The development of an oral formulation remains a challenge that requires a better understanding of the mechanisms involved in the intestinal absorption of this compound. Methods The solubility of lycopene in simulated physiological fluids and bile salt mixed micelle formulations was determined. The extent of intestinal lymphatic transport and the absolute bioavailability of lycopene from a range of biorelevant media was evaluated in a mesenteric lymph duct cannulated anaesthetised rat model. Results The absolute bioavailability of lycopene after 8 h was 1.85 ± 0.39%. The overall extent of the intestinal lymphatic transport was in the range of 0.6–3.4% of the administered dose. A strong positive correlation (r² > 0.9) between intestinal lycopene levels and intestinal triglyceride levels was demonstrated. Conclusions The intestinal lymphatic route is the major uptake mechanism of lycopene from the gastrointestinal tract. Lycopene transport in intestinal lymph was closely associated with triglyceride transport in the lymph. Formulation strategies designed to promote intestinal lymphatic uptake, such as lipid‐based formulations containing long‐chain fatty acids (LCFA) or lecithin, may serve to enhance oral bioavailability of lycopene.     

Effects of lipid vehicle and P-glycoprotein inhibition on the mesenteric lymphatic transport of paclitaxel in unconscious,lymph duct-cannulated rats

The present study examined the effects of lipid vehicle and intestinally based efflux processes on intestinal lymphatic transport of paclitaxel (PTX) in the mesenteric lymph duct-cannulated anesthetized rat model. PTX solution alone, PTX solution pretreated with the P-glycoprotein (P-gp) inhibitor verapamil and/or PTX and a 2:1 (w/w) mixture of linoleic acid:glycerol monooleate were administered intraduodenally to anesthetized rats. Coadministration of a mixture of linoleic acid–monoolein significantly increased the extent of intestinal lymphatic transport of PTX, but it had little impact on the absolute oral bioavailability of PTX. In contrast, pretreatment with verapamil increased both the extent of lymphatic transport (3.5-fold) and absolute oral bioavailability (1.8-fold). Further increase in the lymphatic transport (6.5-fold) and absolute oral bioavailability (1.8-fold) was achieved by the combination of pretreatment with verapamil and coadministration with the linoleic acid–monoolein mixture. These data indicate that the application of lipid vehicle holds promise for selectively targeted lymphatic delivery of PTX. P-gp inhibition can result in both increased intestinal lymphatic levels and absolute oral bioavailability of PTX.     

Estimation of absorption ratios and their variation for orally administered drugs

Summary Differences in the plasma concentrations of drugs after oral administration are caused by two main factors: variation in absorption ratios and in the distribution processes in the body. A new method for the dissection of both types of factors is discussed. The method uses a reference regression of the AUC-values to the corresponding values after intravenous infusion of graded doses. The reference regression is estimated from an appropriate trial. Deviation of the determined AUC-values from the regression curve afford an estimate of the residual variance due to varying distribution volumes or similar random biological effects. For the estimation of absorption ratios after oral administration the drug is given orally to another sample of subjects and their AUC-values are calculated. The deviation of these AUC values due to the above mentioned random effects are simulated using the residual variance of the reference regression, and are subtracted from the observed AUC-values. Then, the differences in the corresponding absorbed doses are transformed by inverting the reference regression. From these doses the empirical distribution function and statistical parameters (e.g. quantiles) are determined. The method has the advantage that no restrictive assumptions are required, such as first order processes, dose linearity, homogeneity of variance or normal distribution of absorption ratios. Its applicability to substances with qualitative differences in their pharmacokinetics is demonstrated by appropriate examples.