苯丙哌林在健康人体内的对映体选择性药物动力学研究

目的　研究苯丙哌林在健康人体内的对映体选择性动力学过程。方法　以非手性HPLC法测定不同时刻血浆样品中苯丙哌林的浓度,再用手性HPLC法测定两对映体的浓度比值,计算得到血浆中(R)-和(S)-苯丙哌林的浓度。结果　6名受试者血浆中S体浓度始终高于R体,S体的AUC_0-t和C_max的均值分别为R体的2.12倍和2.18倍,但二者的T_1/2无显著性差异。服药后0.5 h血浆中S/R对映体浓度比值高达3.8,此后迅速下降,2 h后约为2.2,基本保持恒定到24 h。结论　口服(±)-苯丙哌林后, 两对映体在人体内的药物动力学过程具有显著的立体选择性。     

氢化阿托酸在大鼠体内立体选择性时间药代动力学

以余弦法分析氢化阿托酸(HTA)药代动力学参数证明,下列参数具有昼夜节律:标准明暗周期下,S(+)-HTA的T_1/2β和CL,R(-)-HTA的T_1/2β以及外消旋体的CL和MRT;反相明暗周期下,S(+)-HTA的T_1/2β和AUC,R(-)-体的CL以及外消旋体的CL。下列参数具有立体选择昼夜节律:标准明暗周期下,S(+)-HTA的CL,反相明暗周期下,S(+)-HTA的T_1/2β和AUC以及R(-)-HTA的CL。以外消旋体给药后,大鼠体内由R(-)-体向S(+)-体的转化过程,可出现昼夜节律,在两种明暗周期下,峰值相位均位于黑暗期之末,据此,提出HTA的清晨给药治疗方案。     

中国健康志愿者口服福辛普利的药代动力学研究

目的　研究中国健康志愿者po福辛普利后的药代动力学。方法　10名男性健康受试者po福辛普利20 mg后,用LC/MS/MS法测定不同时间血浆中活性代谢物福辛普利拉浓度,SRM方式选择性检测待测物的特征碎片离子,full-scan ms²方式检测内标物的碎片离子。结果　本法线性良好,精密度、准确度、回收率均符合要求。测得的主要药代动力学参数为：T_1/2=(6.6±1.2) h,　T_max=(3.7±1.1)　h,　C_max=(451.9±251.2)　ng。mL^-1,　AUC_0-∞=(3578.4±2231.2)　h。ng。mL^-1。结论　本实验测得的T_max,C_max和AUC_0-∞均高于文献报道的白人受试者的参数值,而T_1/2显著低于文献值。     

非手性与手性色谱法研究尼莫地平及其对映体在大鼠体内的药代动力学及组织分布

目的研究尼莫地平及其对映体在大鼠体内药代动力学及组织分布特性。方法生物样品在碱性条件下,经正己烷-醋酸乙酯(1∶1)提取。非手性色谱分析用ODS柱(150 mm×4.6 mm ID),以甲醇-水(70∶30)为流动相;手性色谱分析用Chiralcel OJ柱(250 mm × 4.6 mm ID),以正己烷-无水乙醇(85∶15)为流动相;检测波长为236 nm。结果尼莫地平及其对映体分别在非手性及手性色谱系统中分离良好,在血浆及组织匀浆液中线性关系、最低检测限、精密度和准确度均满足分析要求。对映体间主要药动学参数T_max,C_max,AUC和CL_s,S-(-)-尼莫地平为:(2.1±0.3) h,(197±5) μg·L^-1,(656±18) μg·h·L^-1和(0.30±0.03) mL·min^-1,r-(+)-尼莫地平为:(1.7±0.5) h,(128±4)μg·L^-1,(381±8) μg·h·L^-1和(0.53±0.03) mL·min^-1;在主要的效应器官中S-(-)-尼莫地平的浓度高于r-(+)-尼莫地平,在主要消除器官中r-(+)-尼莫地平浓度高于S-(-)-尼莫地平的浓度。结论尼莫地平对映体在大鼠体内药代动力学及组织分布存在着立体差异性。     

手性和非手性联用色谱法研究尼卡地平对映异构体兔体内过程的差异性

目的研究尼卡地平(NCD)对映体在家兔体内药代动力学和组织分布的差异性。方法生物样品在碱性条件下,正己烷-醋酸乙酯(1:1)提取,用手性和非手性联用色谱法进行分离分析。结果尼卡地平及其对映体分别在反相色谱系统及手性色谱系统中分离良好,浓度为55-550ng·mL^-1线性关系良好。对映体的平均日内、日间RSD分别为5.25%和8.97%,回收率分别为99.99%和97.10%;对映体间主要动力学参数T_max,C_max和AUC,S-NCD为(2.49±0.03)h,(134±2)ng·mL^-1和(1082±32)ng·mL^-1·h,R-NCD为(1.24±0.05)h,(109±2)ng·mL^-1和(778±22)ng·mL^-1·h;在主要脏器和细胞中S-NCD的浓度明显高于R-NCD。药代动力学和靶组织分布均有一定差异性。结论尼卡地平对映体兔体内过程包括代谢动力学和靶细胞浓度分布存在着立体差异性。     

高效液相色谱法测定大鼠血浆和子宫中黄体酮及其代谢物的浓度

目的建立高效液相色谱法测定大鼠血浆和子宫样品中的黄体酮及其代谢物20α-羟基黄体酮,并研究大鼠肌肉注射黄体酮后血浆和子宫中的药物代谢动力学。方法样品经液-液萃取后,以乙腈-水(60∶40,pH 4.0)为流动相,用ODS柱进行分离,240 nm检测。以18-甲基炔诺酮为内标。结果血浆中黄体酮C_max为(508±62) μg·L^-1,T_max为(3.2±0.4) h,T_1/2(k_e)为(10±4) h,AUC_0-48h为(5 886±1 573) μg·L^-1·h,子宫中黄体酮T_max为(5.2±1.1) h,C_max(1.7±1.1) μg·g^-1。20α-羟基黄体酮具有与黄体酮相似的T_max。结论该方法简便、准确,可同时测定黄体酮和代谢物,适用于黄体酮及其代谢物20α-羟基黄体酮的药代动力学研究。     

反式曲马多对映体的药代动力学立体选择性

目的:研究反式曲马多对映体:( + )-反式曲马多和( - )-反式曲马多的人体药代动力学。方法:12 名受试者po 多剂量盐酸反式曲马多缓释片,用高效毛细管电泳法测定人血清中反式曲马多对映体的浓度,配对t-检验比较两对映体的血药浓度和药代动力学参数。结果:血药浓度达稳态后不同时间血清中( + )-反式曲马多的浓度均明显高于( - )-反式曲马多的浓度,两对映体的C_max,C_min ,C_av,AUC_0→∞,T_1/2 等药代动力学参数均有显著性差异。结论:人体对( + )-反式曲马多比对( - )-反式曲马多吸收完全、消除慢,反式曲马多对映体有药代动力学立体选择性。     

十名志愿者口服维拉帕米缓释片药代动力学和心电图研究

对10名男性受试者单剂量po240mgVer缓释片药代动力学及心电图变化进行研究。血药浓度—时间数据用零级吸收过程的一室模型拟合,其药代动力学参数:T_max5.9±1.6h;C_max118.9±37.2μg·L^-1;T₁ 5.4±1.5h;k₀30.5±17.5μg·L^-1·h^-1;T_1/210.8±4.9h。PR间期延长有显著意义,血药浓度与PR间期变化满足S 型模型,其药效学参数:EC₅₀ 64.6±16.9μg·L^-1; E_max54±11ms;s 1.68±0.66。     

伏立康唑胶囊人体药动学及相对生物利用度研究

目的 研究健康受试者口服伏立康唑胶囊的药动学和相对生物利用度。方法 20名健康受试者随机服用伏立康唑受试胶囊剂和参比片剂各100 mg,用HPLC-MS/MS测定血浆中伏立康唑的浓度。结果 主要药动学参数,伏立康唑受试制剂与参比制剂的T_max分别为(0.75±0.15)和(0.84±0.25)h,C_max分别为(605.4±136.6)和(595.2±134.7)ng·mL^-1;t_1/2分别为(4.91±1.44)和(5.06±2.06)h,AUC_0-15分别为(1737.6±325.1)和(1750.6±352.8)ng·h·mL^-1。受试制剂与参比制剂的AUC_0-15和C_max经双单侧t检验,T_max经非参数检验,差异均无统计学意义。结论 统计学结果表明,2种制剂生物等效。     

高效毛细管电泳法研究盐酸班布特罗国产胶囊与进口片剂的人体生物等效性高效毛细管电泳法研究盐酸班布特罗国产胶囊与进口片剂的人体生物等效性

目的研究国产盐酸班布特罗胶囊和进口片剂的人体生物等效性。方法采用高效毛细管电泳法测定血浆中班布特罗及其代谢物特布他林的浓度。结果单次口服国产班布特罗胶囊和进口班布特罗片剂后班布特罗的药代动力学参数:AUC0-t分别为(71±18)和(72±13) μg·h·L^-1,实测C_max分别为(8.1±1.8)和(9.2±2.3) μg·L^-1,实测t_max分别为(3.6±1.3)和(3.7±1.0) h。特布他林药代动力学参数:AUC0-t分别为(129±33)和(130±34) μg·h·L^-1,实测C_max分别为(7.8±2.3)和(8.5±2.9) μg·L^-1,实测t_max分别为(5.4±0.8)和(5.6±1.1) h,国产班布特罗胶囊单次给药后的相对生物利用度为(100±16)%(班布特罗),(101±13)%(特布他林)。结论经统计学证明两制剂具有生物等效性。     

Comparison of enantioselective disposition of rabeprazole versus lansoprazole in renal-transplant recipients who are CYP2C19 extensive metabolizers

The purpose of this study was to investigate the comparative pharmacokinetics of rabeprazole and lansoprazole enantiomers in renal-transplant recipients on tacrolimus who were CYP2C19 extensive metabolizers. Sixteen Japanese patients were randomly assigned after renal transplantation to receive repeated doses of one of the following two regimens for 28 days; tacrolimus, mycophenolate mofetil and prednisolone together with either 20?mg of racemic rabeprazole (n?=?8) or 30?mg of racemic lansoprazole (n?=?8). The mean C_max and AUC_0–24 of (R)-lansoprazole compared to (S)-lansoprazole in renal transplant recipients were 12-fold (954?±?522 vs. 167?±?137?ng?ml^?1, respectively) and 6.9-fold (4787?±?3454 vs. 451?±?354?ng?h?ml^?1, respectively) greater, and its elimination half-life was 2.1-fold (2.3?±?1.0 vs. 1.2?±?0.6?h, respectively) longer. In contrast, although the elimination half-life of (R)-rabeprazole was significantly longer than that of the (S)-enantiomer (2.1?±?0.5 vs. 1.3?±?0.9?h, respectively; P?C_max between the (R)- and (S)-enantiomer (186?±?40 vs. 200?±?92?ng?ml^?1, respectively). In conclusion, in renal-transplant recipients who are CYP2C19 extensive metabolizers, there is less stereoselective difference in the pharmacokinetic disposition between the (R)- and (S)-enantiomers of rabeprazole than those of lansoprazole.     

Effect of dimethicone (polysilane gel) on the stereoselective pharmacokinetics of ketoprofen

Objective: Since dimethicone may be employed to improve gastrointestinal tolerability of non steroidal anti-inflammatory drugs (NSAIDs), we studied its influence on the pharmacokinetics of ketoprofen in subjects receiving a single oral dose of racemic ketoprofen. Patients and methods: In a cross-over experimental design, 12 healthy fasting volunteers were given a single oral dose (100 mg) of racemic ketoprofen, administered with or without dimethicone. The kinetic parameters measured were area under the concentration (AUC), maximum peak plasma concentration (C_max), time to reach peak concentration (t_max), elimination half-life (t_1/2), mean residence time (MRT) and urinary excretion for R and S enantiomers. Results: Dimethicone reduced the peak concentration of both R and S ketoprofen by about 10% (P < 0.05) and also induced a slight but non-significant increase in the mean time to achieve peak concentration. However, this treatment had no significant effect on the bioavailability and the elimination of R and S enantiomers, as shown by AUC, t_1/2 and MRT values. The absorption patterns were equivalent for both ketoprofen isomers, since plasma pharmacokinetic parameters were similar. Nevertheless, the urinary recovery was significantly lower for R ketoprofen than for its antipode. The administration of dimethicone did not alter this stereoselectivity. Conclusion: The administration of dimethicone to alleviate the epigastralgic effects related to NSAIDs does not affect the efficacy of the treatment. Dimethicone did not significantly alter the bioavailability of ketoprofen, chosen as an example of an NSAID, especially that of the pharmacologically active S enantiomer. Received: 5 August 1997 / Accepted in revised form: 7 March 1998     

Single-Dose and Steady-State Pharmacokinetics of Diltiazem Administered in Two Different Tablet Formulations

Abstract: Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assesed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in t_max was observed (2.9 ± 1.9 and 6.8 ± 2.6 hr respectively) whereas differences in AUC, t_1/2 and C_max were not significant. The AUC (mean ± S.D.) values following single dose administration of Cardil® and Cardizem® were 678.4 ± 321.5 and 948.6 ± 580.6 ng · ml^-1 · hr respectively. The mean and the 95% confidence limits for the observed ratio AUC_Cardil/ AUC_Cardizem are 0.89 and 0.44-1.34 respectively. At steady-state a significant difference between C_max/C_min and t_max was seen C_max/C_min being 4.9 and 3.2 respectively and T_max being 2.7 ± 2.0 and 6.0 ± 2.8 hr respectively, whereas C_max and AUC did not differ significantly. The AUC (mean ± S.D.) values in steady state of Cardil® and Cardizem® were 880.1 ± 399.8 and 1056.8 ± 509.8 ng · ml^-1 · hr respectively. The mean and the 95% confidence limits for the observed ratio AUC_Cardil/AUC_Cardizem are 0.96 and 0.66-1.26 respectively. Although the observed ratios AUC_Cardil/AUC_Cardizem in both the single-dose and the steady-state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).     

盐酸普萘洛尔缓释片与常释片的生物利用度比较研究

目的：通过双交叉试验证明盐酸普萘洛尔缓释片有缓释作用。方法：用HPLC方法,测定血清中普萘洛尔浓度,进行盐酸普萘洛尔缓释片与常释片的生物利用度比较及峰谷浓度波动研究。结果：12位健康男性受试者一次交叉口服缓释片和常释片(均为40 mg)后的C_max分别为62.4±23.3和95.9±12.6 ng.mL^-1,AUC分别为360.2±80.6和383.5±74.2 ng.h.mL^-1,缓释片相对于常释片的相对生物利用度为95%;12位受试者连续服缓释片和常释片后平均稳态浓度分别为42.2±12.2和32.7±7.1 ng.mL^-1,波动度(DF)分别为0.90±0.35和2.09±0.34。结论：两种制剂具生物等效性,且缓释片比常释片有峰谷浓度差异小、血药浓度波动幅度小的特点。     

Pharmacokinetics of Ibuprofen Enantiomers in Humans Following Oral Administration of Tablets with Different Absorption Rates

Ibuprofen (IB) is a racemic drug and is administered as such. While activity is due mainly to the S enantiomer, pharmacokinetic interpretations, as well as criteria to assess the bioequivalence of IB formulations, are based on measurements of the total (S + R) drug concentrations. IB enantiomers possess different disposition properties mainly as a result of R-to-S isomeric bioinversion. Inversion is maximal during the absorption phase, suggesting, perhaps, involvement of a presystemic process. This concept was evaluated in healthy subjects by crossover administration of four IB tablets having different absorption rates. The plasma concentrations of the individual isomers were measured using a stereospecific gas chromatographic assay. Differences among the products were insignificant with respect to the extent to the absorption. The S:R concentration ratios rose for 4 to 6 hr and then remained relatively unchanged. This observation was consistent with equal terminal t _1/2 values for the enantiomers. There were significant differences between the peak times (T _max) of the products. The S:R ratios of the concentrations at T _max of S and AUC also differed; significant positive correlations were found between T _max and the S:R ratios of C _max. Thus the extent of R-to-S inversion, and hence the potency of a racemic dose of IB, may be absorption rate dependent.     

硫酸沙丁胺醇缓释胶囊人体药代动力学和生物利用度

目的　研究健康受试者单剂量和多剂量口服硫酸沙丁胺醇缓释胶囊的人体生物利用度和药代动力学。方法　以英国Glaxo公司生产的硫酸沙丁胺醇控释片为参比制剂,HPLC-UV法测定20名健康男性志愿受试者按交叉试验单剂量和多剂量口服硫酸沙丁胺醇缓释胶囊和控释片后血浆中沙丁胺醇的浓度。结果　单剂量服用硫酸沙丁胺醇缓释胶囊和控释片后,二者的C_max,T_max和T_1/2均无显著性差异,缓释胶囊的相对生物利用度为99.68%±10.27%。多剂量给药达稳态时,缓释胶囊和控释片的C^ss_max,C^ss_min,波动度(DF),均无显著性差异。结论　两种制剂具有生物等效性,缓释胶囊有与控释片相似的缓释特征。     

Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers

Objective To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the β1 adrenoceptor blocker talinolol. Methods The study was conducted in a self-controlled, two-period experiment with a randomized, open-labeled design, using 12 healthy volunteers and a wash out period of 1 week between the administration of a single oral dose of 50 mg talinolol and the concomitant administration of curcumin (300 mg day⁻¹ for 6 days) and a single oral dose of 50 mg talinolol on the seventh day. Concentrations of talinolol were measured in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles, all pharmacokinetic parameters were calculated using DAS (ver. 2.0) software, and comparisons of mean values were analyzed by the Wilcoxon signed rank test. Differences were considered to be significant at p < 0.05 (two-sided test). Results The consumption of curcumin for 6 days reduced the area under the curve (AUC) from predose to infinity () of talinolol from 1860.0 ± 377.9 to 1246.0 ± 328.2 ng.h mL⁻¹, the highest observed concentration values (C_max) were significantly decreased from 147.8 ± 63.8 to 106.4 ± 39.9 ng mL⁻¹, and the CL/F was increased from 27.9 ± 5.5 to 43.1 ± 13.4 L.h⁻¹ (p < 0.05). There was no significant difference in sampling time for C_max (t_max) and elimination half-life (t_1/2) values between the two periods (p > 0.05). The interindividual variability in AUC_0–60 and C_max of talinolol was comparable in two study periods; the coefficient of variance (CV) of AUC_0–60 and C_max was 26 and 40% after curcumin versus 21 and 43% after talinolol alone, respectively. Conclusion We suggest that the reduced bioavailability of talinolol is most probably due to the low intraluminal curcumin concentration, or possibly due to the upregulation of further ATP-binding cassette transporters, such as MRP2, in different tissues.     

Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite,norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (C_max) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T_max) and the terminal half-life (t_1/2) of verapamil in the presence of lovastatin. The AUC and C_max of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.