药代动力学-药效动力学结合模型在中药研究中的应用

药代动力学-药效动力学(Pharmacokinetic-pharmacodynamic,PK/PD)结合模型是研究中药体内代谢过程、药物效应及二者联系的有效工具,对于中药作用机制研究、临床用药优化有重要的参考价值。建立能体现中医药特色的PK/PD结合模型十分必要。该文针对目前PK/PD结合模型在中药研究领域的应用现状作了系统的阐述,并就中药效应物质基础的确定、效应指标的选择等关键问题进行探讨并提出建议,以期为今后的相关研究提供参考。     

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。     

药代动力学药效动力学结合模型研究进展

药代动力学和药效动力学共同构成了现代药理学研究的基础。PK/PD模型是将两者相结合,以说明给予某一剂量后所引起的药理作用的时间过程。研究PK/PD关系不但有助于正确指导临床用药,还可以用于探讨药物作用机制、新药评估以及新制剂的开发等。本文就近些年来PK/PD模型在药理学和毒理学,临床应用以及新药开发等方面的研究进展作一简要的综述。     

瑞格列奈对吡格列酮及其主要活性代谢物在健康人体的药代动力学影响

目的 研究瑞格列奈(短效促胰岛素释放剂)对吡格列酮(胰岛素增敏剂)及其主要活性代谢物在健康人体中的药代动力学影响.方法 采用随机交叉试验设计,将12名男性健康受试者随机分为吡格列酮单药给药组和吡格列酮与瑞格列奈片合并给药组,清洗期为2周.采用HPLC-MS法测定吡格列酮及其代谢产物M-Ⅳ、M-Ⅲ的血药浓度.结果 合并瑞格列奈给药后,PIO、M-Ⅳ、M-Ⅲ的AUC0-τ分别为(6.15±2.71),(12.88±5.16),(5.72±3.06)μg·h·mL-1;Cmax分别为(626.77±208.21),(272.24±153.76),(132.04±78.42)ng·mL-1;tmax分别为1.0(0.5～3.0),12.0(12.0～ 72.0),12.0(12.0～ 15.0)h,与吡格列酮单药给药组相比,均无显著性改变(P>0.05).吡格列酮单药和吡格列酮与瑞格列奈片合用在健康人体的药代动力学行为相近.结论 瑞格列奈对吡格列酮及其主要活性代谢物在健康人体的药代动力学无显著影响.     

药代动力学和药效动力学理论指导系统性抗真菌治疗

侵袭性真菌感染多见于有严重器官疾病、长期使用抗菌药物或免疫抑制人群,是住院患者常见的感染之一。目前,用于抗真菌治疗的药物数量较少,毒性较高。针对不同人群正确地进行抗真菌药物种类和剂量的选择非常重要。目前常用的抗真菌药物共有4类,它们是多烯类(两性霉素B)、唑类(氟康唑、伊曲康唑、伏立康唑)、嘧啶类(氟胞嘧啶)     

罗红霉素健康人体药代动力学研究

本实验采用微生物法测定罗红霉素血药浓度，研究了10名中国男性健康志愿者口服150mg罗力得后的血浆罗红霉素药代动力学。结果表明，罗红霉素的体内过程符合二房室模型，其主要药动学参数为tmax1．8±0．5h，Cmax4．06±0．89μg／ml，t1／2a1．09±0．51h，t1／2β9．71±2．36h，Vc／F20．1±5．03L，CL／F4．52±0．66L／h，AUC35．6±4．19mg／mlh。说明罗红霉素口服后具有吸收快、消除慢和峰浓度较高等特点。     

苦参碱及氧化苦参碱的药代动力学与药效动力学

以QTc延长率为效应指标,用药代动力学-药效动力学结合模型对苦参碱、氧化苦参碱iv后在免体内的处置和效应动力学作定量分析,两药的血浓时程均符合二房室模型,两药的效应与效应室浓度之间的关系均符合S形E_max模型。两药彼此的药动学和药效学性质均有明显差异,但它们各自的劳动学和药效学性质在所用剂量范围内均为非剂量依赖性。     

关于瑞格列奈对吡格列酮及其主要活性代谢物在健康人体的药代动力学影响

目的研究探讨关于瑞格列奈对吡格列酮及其主要活性代谢物在健康人体的药代动力学影响的研究。方法选取20名健康受试者高脂饮食后随机交叉口服单独吡格列酮30mg和吡格列酮30mg联合瑞格列奈0.5mg,清洗周期为2周。按顺序分为对照组和观察组。采用HPLC-MS法测定吡格列酮及其主要活性代谢产物M-Ⅳ、M-Ⅲ的血药浓度。结果给药吡格列酮15mg联合瑞格列奈药0.5mg(观察组)后,抗糖尿病药吡格列酮(PIO)、羟基吡格列酮(M-Ⅳ)、酮基吡格列酮(M-Ⅲ)的tmax(h)分别为(2.0±1.4)、(40.2±29.9)、(13.2±1.4);AUC0-324[μg/(L h)]分别为(6.42±2.28)、(13.08±5.41)、(6.01±2.91);Cmax(μg/L)分别为(641.03±198.87)、(301.16±102.21)、(141.09±80.31)。与吡格列酮单药给药组相比,均无显著性差异(P>0.05)。吡格列酮单药和吡格列酮与瑞格列奈片联合给药在健康人体的药代动力学行为基本相近。结论瑞格列奈对吡格列酮及其主要活性代谢物在健康人体的药代动力学基本无显著性影响。     

瑞格列奈分散片在健康人体中的相对生物利用度研究

目的研究瑞格列奈分散片与瑞格列奈片在中国男性健康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,20名健康男性受试者分别口服受试制剂瑞格列奈分散片和参比制剂瑞格列奈片4mg,采用LC-MS／MS法测定给药后不同时间瑞格列奈的血药浓度。利用DAS2．0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等效性评价。结果受试制剂与参比制剂中瑞格列奈的Cmax分别为（110．8±59．9）、（101．5±48．8）μg·L^-1;tmax分别为（0．54±0．20）和（0．65±0．34）h;AUC0～8分别为（112．5±38．4）和（110．8±42．O）μg·h·L^-1;AUC0-∞分别为（114．1±38．8）和（112．7±41.8）μg·h·L^-1。受试制剂对参比制剂的相对生物利用度F（以AUC0-8作为评价依据）为（105．0±25．0）％。结论受试制剂与参比制剂具有生物等效性。     

马来酸替加色罗片健康人体药代动力学试验

目的进行健康志愿者马来酸替加色罗片单剂和多剂给药的药代动力学研究.方法采用LC-MS法测定替加色罗经时血浓度,计算替加色罗主要药代动力学参数,了解替加色罗口服给药在人体分布、消除、蓄积规律.结果及结论采用LC-MS方法测定替加色罗血浓度,灵敏度高,回收率和日内日间变异符合生物样本研究要求.     

酰托普利在健康男、女受试者体内的药代动力学研究

目的：研究新型血管紧张素转换酶抑制剂酰托普利在健康男、女受试者体内的药代动力学和安全性。方法：10名健康男、女受试者（男、女各半）连续口服酰托普利30mg（bid,7d）,另有10名健康男、女受试者（男、女各半）分别在空腹和进食标准餐后单剂量口服酰托普利60mg,按规定时间点取血并测定血浆药物浓度,采用WinNonlin软件计算药代动力学参数。结果：受试者首次和末次口服30mg酰托普利后的平均Cmax分别为（279±100）、（299±101）μg/L,tmax分别为（1.2±0.5）、（1.2±0.3）h,t1/2分别为（1.3±0.9）、（1.3±0.5）h,AUC0-t分别为（421±107）、（461±152）μg·L^-1·h,在二者之间无统计学差异。比较受试者单剂量空腹和餐后口服酰托普利60mg,tmax明显延后,Cmax有所降低,其他参数AUC、t1/2等在两种给药方式间无差异。各试验组中男、女受试者的药动学参数均无统计学差异。结论：本研究未观察到酰托普利有药物蓄积现象,进食影响该药的吸收速率,不影响其吸收程度,其体内过程不受性别差异的影响。     

α－羧乙基锗倍半氧化物胶囊在健康人中的药物动力学参数测定

采用苯基荧光酮分光光度法测定了６例健康人单剂口服２０ｍｇ／ｋｇα－羧乙基锗倍半氧化物后血清药浓度，人体内药物动力学过程符合单室模型，主要参数Ｋ０．３２１ｈ－１，Ｋａ１．２２１ｈ－１，Ｔ１／２２．１６１ｈ，Ｔｍａｘ１．８８５ｈ，Ｃｍａｘ１２．７６１μｇ／ｍｌ。     

Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects

Summary The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 µg, 150 µg and 250 µg in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19–22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (C_max) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 µg) also produced significant reductions in plasma catecholamine levels.     

甲磺酸帕珠沙星在中国健康受试者体内的药物代谢动力学研究

目的采用高效液相色谱法测定甲磺酸帕珠沙星的药物代谢动力学。方法样品经50%三氟醋酸直接沉淀蛋白后,用Hypersil BDS柱分离,以氧氟沙星为内标,采用紫外检测。结果日内、日间误差分别<6.5%和<15%,平均回收率为58.05%±4.26%。在47~24 080 ng.mL-1血浆浓度范围内呈线性关系(r2=0.997)。最低检测浓度为25 ng.mL-1。结论此法操作简便、快速。应用此法研究了30名健康志愿者30 min静脉滴注不同剂量注射用甲磺酸帕珠沙星试验制剂(0.5、1.0、1.5 g加入100 mL 0.9%氯化钠溶液中)后的药物动力学。     

Pharmacokinetic and pharmacodynamic characterization of gliclazide in healthy volunteers

Pharmacokinetic and pharmacodynamic properties of gliclazide were studied after an oral administration of gliclazide tablets in healthy volunteers. After an overnight fasting, gliclazide tablet was orally administered to 11 volunteers. Additional 10 volunteers were used as a control group (i.e., no gliclazide administration). Blood samples were collected, and the concentration determined for gliclazide and glucose up to 24 after the administration. Standard pharmacokinetic analysis was carried out for gliclazide. Pharmacodynamic activity of the drug was expressed by increase of glucose concentration (deltaPG), by area under the increase of glucose concentration-time curve (AUC(deltaPG)) or by the difference in increase of glucose concentration (D(deltaPG)) at each time between groups with and without gliclazide administration. Pharmacokinetic analysis revealed that Cmax, Tmax, CL/F (apparent clearance), V/F (apparent volume of distribution) and half-life of gliclazide were 4.69+/-1.38 mg/L, 3.45+/-1.11 h, 1.26+/-0.35 L/h, 17.78+/-5.27 L, and 9.99+/-2.15 h, respectively. When compared with the no drug administration group, gliclazide decreased significantly the AUC(deltaPG) s at 1, 1.5, 2, 2.5, 3 and 4 h (p<0.05). The deltaPGs were positively correlated with AUC(gliclazide) at 1 and 1.5 h (p<0.05), and the correlation coefficient was maximum at 1 h (r = 0.642) and gradually decreased at 4 h after the administration. The AUC(deltaPG)s were positively correlated with AUC(gliclazide) at 1, 2, 3 and 4 h (p<0.05), and the maximum correlation coefficient was obtained at 2 h (r=0.642) after the administration. The D(deltaPG) reached the maximum at 1 h, remained constant from 1 h to 3 h, and decreased afterwards. Therefore, these observations indicated that maximum hypoglycemic effect of gliclazide was reached at approximately at 1.5 h after the administration and the effect decreased, probably because of the homeostasis mechanism, in health volunteers.     

Bioequivalence study of two enalapril maleate tablet formulations in healthy male volunteers Pharmacokinetic versus pharmacodynamic approach

Objective: Two different conventional release enalapril maleate tablet formulations were evaluated for their relative bioavailability (Eupressin tablets 10 mg, Biosintética as the test formulation vs Renitec tablets 10 mg Merck Sharp & Dhome, as the reference formulation). A single 20 mg oral dose of each preparation was administered to 18 healthy male adult volunteers and their bioequivalence was assessed by comparing the serum enalaprilat and total enalapril (enalaprilat plus enalapril maleate) concentration-time curves. Angiotensin converting enzyme (ACE) activity was also quantified in each serum sample. Results: The pharmacokinetic parameters obtained for each formulation were the area under the time-concentration curve from 0 to 24 h (AUC_[0–24]), maximum concentration C_max and the time at which it occurred (t_max). When serum enalaprilat concentration-time curves were employed to assess bioequivalence, the formulations were bioequivalent in the extent but not in the rate of absorption. However, no difference in either the extent or the rate of absorption were observed when serum total enalapril vs time curves were analysed. ACE activity-time curves were similar for both formulations and showed that ACE was 90% inhibited 3–5 h after enalapril administration, and till approximately 50% after 24 h. At that time, circulating enalaprilat and total enalapril levels were less than the tenth of C_max. Conclusion: The results show that complete bioequivalence of the two formulations can be concluded from serum total enalapril concentration data, and that serum ACE activity is not a suitable pharmacodynamic variable for assessing bioequivalence. Received: 29 May 1995/Accepted in revised form: 30 October 1995     

Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers

AIMS

Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug.

METHODS

This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h).

RESULTS

Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration–time curve (AUC_τ) and maximum concentration (C_max), with changes of −55% [90% confidence interval (CI) −62, −45] and −36% (90% CI −49, −21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUC_τ (−7%; 90% CI −23, 13) and increased C_max (23%; 90% CI −1, 53), while increasing efavirenz AUC_τ (17%; 90% CI 6, 29) and not changing C_max when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz.

CONCLUSIONS

When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered.
• Furthermore, voriconazole increases the systemic exposure of efavirenz.
• Co-administration was therefore initially contraindicated.

WHAT THIS STUDY ADDS

• The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety.
• Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication.