大鼠淋巴结利福平浓度的测定

（1. ［摘要］目的研究大鼠口服利福平后淋巴结的药物浓度变化特点，为淋巴结结核治疗方法的改进提供理论依据。方法Wistar大鼠15只，随机分为3组，每组5只，禁食12 h后，喂服利福平10 mg&;#8226;kg-1，分别于给药后2，8，24 h行眼球摘除取血并摘取肠系膜淋巴结，采用高效液相色谱法测定不同时间的腹腔淋巴结药物浓度及血清药物浓度。结果血清利福平与淋巴结利福平浓度呈良好线性关系，日内、日间RSD均＜7%，能满足测定要求。各时间点利福平淋巴结浓度达到其抑菌浓度水平，但均显著低于血药浓度(P＜0.01)。结论该方法准确度高，是一可靠的测定淋巴结利福平浓度的方法；淋巴结内利福平浓度显著低于血药浓度，淋巴结结核的治疗需要提高淋巴结局部药物浓度。     

结核患者各种体液中利福平浓度及其相关性研究

目的:建立高效液相色谱法测定结核病患者血浆、胸水、腹水利福平浓度的方法,进行药物浓度相关性研究.方法:对34例住院患者血浆、胸水、腹水中利福平浓度测定结果进行分析;高效液相色谱法测定采用C18色谱柱分离,波长在333 nm处检测,柱温20℃.结果:线性关系良好(r＝0.9993),日内、日间RSD均＜10%,能满足测定要求.服药2 h后利福平浓度,血浆中最高,胸水、腹水中较低,而12 h后血浆中药物浓度在最低检测浓度以下,胸水、腹水中浓度仍远大于最低抑菌浓度(0.02 μg•mL 1).结论:服药后2 h,血浆与胸水及腹水浓度呈一定正相关;每日空腹使用利福平1次,靶部位浓度即可维持在治疗浓度水平.     

双环醇对利福平大鼠体内药动学的影响

目的:研究双环醇对利福平血药浓度及药动学的影响。方法:12只Wistar大鼠随机分为利福平(对照)组和双环醇+利福平(实验)组共2组,双环醇与利福平的剂量分别为15.85、63.4mg.kg-1,每天1次,连续给药4d。在第4天给药前和给药后0.25、0.5、1、1.5、2、4、6、8、12、24h取血,应用高效液相色谱法测定2组利福平的血药浓度,并计算药动学参数。结果:2组各时间点利福平血药浓度及药动学参数之间比较均无显著性差异(P>0.05)。结论:双环醇与利福平合用于大鼠体内后对利福平药动学无显著影响。     

高效液相色谱法测定利福平血清和关节腔液浓度

目的建立测定血清及关节腔液中利福平的高效液相色谱法,并以此法考察单剂量口服利福平后关节腔液中药物的分布情况。方法血清加抗氧剂维生素C后,用乙酸乙酯提取浓集进样,采用C18柱(150×3.9mm4μ),以甲醇-0.025mol/LNaAc(用HAc调到pH7.0)(62∶40)为流动相,氯氮([HT6”,5”K〗艹)/(卓)为内标,紫外检测波长为334nm。测定单剂量口服利福平2h后血清及关节腔液中的利福平浓度。结果血清利福平在0.5～20μg/ml、关节腔液在0.5～10μg/ml范围内浓度与峰面积比线性关系良好。两者回收率分别为100.9%和99.3%,日内、日间误差两者均≤6%。给药2h后,关节腔药物浓度只为同期血清浓度的22%左右。结论;本法准确、灵敏,适用于治疗药物监测和药动学研究。利福平用于关节结核的治疗应给予较大剂量。     

柑桔素抑制CYP450 3A4活性并减轻异烟肼和利福平合用的肝细胞毒性

目的研究柑桔素对异烟肼和利福平导致肝毒性增加的防治作用及CYP3A4在其中的作用机制。方法将培养的QSG-7701人肝细胞培养液中分别加入异烟肼和利福平,同时加入不同剂量(1、5、25mg.L-1)的柑桔素后继续培养48h。分别收集药物处理后的培养液和细胞,将细胞裂解后,用比色法分别测定培养液和细胞裂解液中的乳酸脱氢酶的活性,计算细胞外和细胞内乳酸脱氢酶的比值。药物处理48h后,将细胞与CYP3A4作用底物咪达唑仑共同孵育2h,采用高效液相色谱质谱联用法测定咪达唑仑浓度的变化,计算细胞内CYP3A4的活性。结果与对照组比较,异烟肼和利福平合用使肝细胞乳酸脱氢酶释放增加,CYP3A4活性增强;5、25mg.L-1的柑桔素均可减弱异烟肼和利福平升高乳酸脱氢酶的作用,但未使其恢复正常水平;5mg.L-1的柑桔素还减弱了异烟肼和利福平合用导致CYP3A4活性增强的作用,但也未使其恢复正常水平。结论异烟肼和利福平合用对人肝细胞具有细胞毒性作用,柑桔素可以通过抑制其升高CYP3A4活性的作用而减轻肝细胞的损伤。     

利福平栓剂的制备及其体外溶出度测定

目的:制备利福平栓剂并测定其体外溶出度。方法:以明胶及甘油等为基质制备利福平栓剂;采用紫外分光光度法测定利福平栓剂的溶出度,并与市售利福平胶囊比较。结果:利福平检测浓度在10.0~60.0μg.mL-1范围内线性关系良好(r=0.9999),平均回收率为99.87%(RSD=0.42%,n=6)。利福平栓剂及胶囊45min时体外溶出度分别为(89.9±0.97)%、(79.8±1.14)%。结论:该制剂制备方法简单,成模性好,成本低,体外溶出度较高。     

尿中利福平排泄情况分析

利福平是治疗结核病的重要抗生素。有关它在体内的代谢情况,有人曾做过一些研究.为了进一步了解利福平的代谢情况,我们也进行了一些血液及尿液的分析。本文提供了一个尿中利福平的化学分析法,并测定了利福平在尿中的排泄情况.     

异福片中利福平的生物等效性评价

目的 :通过利福平的体内动力学评价异福片中利福平的质量。方法 :采用反相高效液相色谱法测定24名志愿受试者单剂量口服异福片、胶囊后 ,利福平血药浓度的变化。结果 :异福片、胶囊中利福平的AUCn→24 分别为 (60 79±18 82) μg/(ml·h)、(62 28±18 22) μg/(ml·h) ,Tmax 分别为 (1 94±0 27)h、(2.02±0 38)h ,Cmax 分别为 (13 11±3 48) μg/ml、(13 20±2 77) μg/ml。结果表明 ,二者AUC、Tmax、Cmax 均无显著性差异 ,异福片中利福平相对生物利用度为 (102 58±9 33) %。结论 :只要控制好生产条件 ,片剂的内在质量完全可以保证     

利福喷丁胶囊在肺结核患者体内的药物动力学观察

测定肺结核患者单剂量po利福喷丁后的血浆药物浓度,观察其药物动力学参数.12名肺结核患者单剂量po利福喷丁胶囊450mg,以利福平为内标,用高效液相色谱法测定服药后的经时血浆药物浓度,并用PKBP-N1药物动力学程序拟合处理及计算药物动力学参数.结果:利福喷丁胶囊po符合血管外给药一室开放模型,吸收与消除半衰期分别为1.59士0.35h和16.06士1.97h,达峰时间为6.10士0,76h,峰浓度为6.32士0.68μg/ml,药-时曲线下面积为141.7±21.3μg·h/ml.提示:肺结核患者po利福平喷丁胶囊的药物动力学参数与文献报道的健康志愿者无显著性差异.     

利福平注射液在结核病患者体内的药代动力学研究

测定利福平注射液的药代动力学。12例结核病患者静脉滴注300mg或600mg利福平注射液后,甲荧光偏振免疫法测定血药浓度。静脉给予利福平的平均血药峰浓度分别为(9.0±3.0)μg/mL和(17.5±5.0)μg/mL,机体清除率分别为(0.19±0.6)L/(kg h)和(0.14±0.03)L/(kg h),稳态分布容积为(0.66±0.14)L/kg和(0.64±0.1)L/kg。     

国产异福片、胶囊人体生物利用度研究

目的　研究国产异福片 (T1)、胶囊 (T2 )与进口片 (R)在健康人体内的生物利用度和药动学比较。方法　 2 1名受试者采用随机数字分组自身交叉对照给药方案。单剂量口服卫非宁片 (R :含利福平 (RFP) 6 0 0mg ,异烟肼 (INH) 4 0 0mg)和国产试验药 (均含利福平、异烟肼各 6 0 0mg及 30 0mg) ,用HPLC分别测定利福平和异烟肼血药浓度变化。用 3P97计算机程序求药动学参数。结果　参比药卫非宁片与T1和T2 三种制剂中的利福平 (RFP)的主要药动学参数为t1/ 2 分别为 (3.0 1± 0 .86 ) (R) ,(3.0 2± 0 .82 ) (T1)和 (2 .81± 0 .6 3) (T2 ) ;Cmax分别为 (12 .4 4± 4 .79) ,(11.77± 4 .39) ,(13.32± 4 .91) μg/mL ;Tmax为 (1.71±0 .6 2 ) ,(1.79± 0 .82 )和 (1.83± 0 .76 )h ;AUC0～t为 (79.2 6± 2 5 .89) (R) ,(77.71± 2 3.32 ) (T1)和 (78.0 1± 2 6 .76 ) μg·h·mL-1(T2 ) ;T1和T2 的相对生物利用度为 (99.4 8± 15 .0 5 ) % (T1)和 (99.16± 14 .12 ) % (T2 )。异烟肼的主要药动学参数为t1/ 2 :(2 .2 4± 0 .96 ) ,(2 .32± 0 .95 )和 (2 .32± 1.0 4 )h ;Cmax:(8.0 4± 3.6 5 ) ,(6 .15± 1.5 2 )和 (6 .12± 2 .19) μg/mL ;Tmax:(0 .90± 0 .4 8) ,(0 .79± 0 .5 4 ) ,(0 .71± 0 .30 )h ;AUC0     

利福平的剂型与生物利用度的研究

本文研究了利福平不同剂型的生物利用度。用狗,家兔和健康人做了对比实验,发现利福平的脂肪性基质口服制剂的生物利用度较胶囊剂、片剂、栓剂都高,且对肝脏的毒性也较小。用非模型矩量分析法求出的AUC~(0→∞)和MRT可知:450mg的脂肪性基质口服制剂可以获得与600mg胶囊剂相似的血药水平。因而可以推测利福平的脂肪性基质口服制剂的剂量较胶囊剂可降低1/4—1/3。     

The effect of sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin tablets

The effect of Sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin was investigated. The bioavailability of ampicillin was determined using the urinary excretion method. The urinary levels of ampicillin were measured chemically. Bacampicillin capsules were administered: (i) under different dietary conditions; and (ii) on an empty stomach together with chloroquine phosphate tablets. Unlike the case of ampicillin capsules, neither food nor chloroquine affected the bioavailability of ampicillin from bacampicillin capsules. The difference between ampicillin and bacampicillin capsules with respect to the effect of food and chloroquine on ampicillin bioavailability is discussed.     

头孢拉定胶囊溶出度、体内生物利用度及其相关性研究

本文对不同厂家头孢拉定胶囊溶出度、体内生物利用度进行了比较试验,表明头孢拉定胶囊的处方、工艺、辅料、空胶囊对于头孢拉定溶出度、生物利用均有影响,体外溶出度与体内生物利用度有一定的相关性。     

In vitro evaluation of food effect on the bioavailability of rifampicin from antituberculosis fixed dose combination formulations

Rifampicin is one of the major first line anti-tuberculosis drugs used in the therapy of tuberculosis. In literature, there are conflicting reports regarding effect of food on the bioavailability of rifampicin. In vitro, effect of food on the bioavailability can be studied by simulating in vivo conditions in dissolution fluid hence, to understand the variable effect of food on rifampicin release, dissolution studies were done by simulating in vivo conditions after meal intake. In this study, we assessed the effect of hydrodynamic stress in presence of food and meal composition on two rifampicin containing fixed dose combination formulations by carrying out dissolution at different agitation rates (simulation of fasted and fed state) as well as in the presence of different percentage of oil (fatty food). Agitation intensity as well as presence of oil did not had any influence on rifampicin release from formulation A. This formulation had shown excellent release characteristics at all the conditions studied. Whereas, formulation B showed agitation rate dependent release and also release was affected in presence of oil. Hence, it is concluded that food may not have any effect on the release of rifampicin from the formulation and subsequently on its bioavailability if the formulation has excellent release profile (>85% release in 10 min). Further, effect of food on the rifampicin release was a function of dosage form characteristics such as disintegration time and dissolution rate, which will subsequently affect the release behavior of a formulation in presence of food.     

Bioequivalence trials of rifampicin containing formulations: extrinsic and intrinsic factors in the absorption of rifampicin.

Rifampicin shows variable bioavailability from solid oral dosage forms and the reasons for this variable absorption reported in literature varies from extrinsic formulations factors to intrinsic variability in rifampicin absorption. Hence, we have undertaken a systematic and comprehensive evaluation of all the factors to study contribution of all the factors on rifampicin absorption. As a first step, data from eight bioequivalence studies conducted at National Institute of Pharmaceutical Education and Research (NIPER) bioavailability center was compared across the trials to understand the effect of extrinsic/intrinsic factors on the bioavailability of rifampicin, isoniazid and pyrazinamide. Out of eight fixed dose combination (FDC) formulations, six formulations were bioequivalent for rifampicin to separate formulations whereas one formulation was below and one was above the limits of bioequivalence. It was observed that more variability in rifampicin blood levels is associated with FDC formulations when compared to rifampicin-only formulations and was attributed to complexity involved in the manufacturing of FDCs. Further, one of the rifampicin-only capsule showed unexpectedly lower plasma levels indicating role of physical characteristics of rifampicin bulk material. It was also seen that rifampicin shows dose-dependent pharmacokinetics even at the modest increase in dose due to saturation of efflux system at absorption site and metabolizing enzymes for elimination. Other components of FDC formulations such as isoniazid and pyrazinamide due to high solubility and permeability have shown very less variability and were bioequivalent to separate formulations even from formulations those were failed for rifampicin. The comparison of data across the trials suggested that rifampicin bioavailability problem is more attributable to the extrinsic factors such as formulation or rifampicin bulk material rather than intrinsic variability of rifampicin absorption.     

Study of the bioavailability of different formulations of 8-methoxypsoralen in the dog

The absolute bioavailability of 8-methoxypsoralen in gelatin capsules and as a solution was studied in dogs. A dose of 2 mg kg-1 was given. Both for the solution and the gelatin capsules, a large variation in bioavailability was found between the different dogs. For the gelatin capsules in 1 dog out of 4 an absolute bioavailability of more than 100 per cent was found; for the solution a bioavailability of more than 100 per cent was found in all 4 dogs. Resorption was more rapid and bioavailability higher for the solution than for the gelatin capsules. Relative bioavailability of an emulsion and of a solution of 8-methoxypsoralen was studied in 2 dogs. A faster resorption and a higher bioavailability were found for the solution.     

In vitro evaluation of fixed dose combination tablets of anti-tuberculosis drugs after real time storage at ambient conditions

Rifampicin exhibits variable bioavailability from solid oral dosage forms and this problem is more apparent when it is formulated as fixed dose combination (FDC) in presence of other first-line anti-tuberculosis drugs. To determine the cause of variable bioavailability, the aging effect on physical and chemical performance of rifampicin from FDC formulations after real time storage at the ambient conditions was investigated. For this purpose, six FDC formulations from different manufacturers were stored at ambient conditions (20-35 degrees C, with no control of humidity) in the final packing for a period of 16-38 months and its in vitro quality control tests for rifampicin were compared with the initial performance of these tablets. None of the formulations have shown significant weight gain/loss and the assay values were within the pharmacopeial limits when evaluated by a stability indicating method. Further storage had no effect on physical performance of FDC tablets as indicated by unaltered dissolution profiles. Formulation reevaluation after real time storage at the ambient conditions for 16-38 months indicated that rifampicin containing FDC formulations are stable throughout its shelf life and instability is not a cause of variable bioavailability.     

Pharmacokinetics and relative bioavailability of oral theophylline capsules

The oral bioavailability of liquid-filled theophylline capsules relative to a nonalcoholic aminophylline solution was determined in normal volunteers. In addition, theophylline absorption and elimination kinetics were reexamined. There were no statistically significant differences between the bioavailability of capsules and liquid as measured by the area under the curve (AUC) from time 0 leads to infinity (p greater than 0.05). The bioavailability parameters of Cmax, tmax, and AUC were determined from actual serum theophylline concentration-time data and from a nonlinear least-squares fit of the serum concentration-time data. Theophylline absorption from the capsules was noticeably faster than from the liquid in most subjects, although the differences in absorption rates were not significantly different (p greater than 0.05). The determined apparent volume of distribution, elimination half-life, and plasma clearance of theophylline were similar to values reported by other investigators. Marked inter- and intraindividual variations in the elimination half-life were noted.