Pharmacokinetic Differences between Pantoprazole Enantiomers in Rats

Purpose The purpose of this study was to quantitatively clarify the contribution of the absorption, protein binding, and metabolism of cytochrome P450 enzymes to the enantioselective pharmacokinetics of pantoprazole enantiomers in rats. Methods The enantioselective pharmacokinetics of pantoprazole enantiomers was estimated by an oral administration of racemic pantoprazole to rats. The pharmacokinetic differences between pantoprazole enantiomers were evaluated by the experiments of the in situ perfusion into rat small intestine, the protein binding, and the in vitro metabolism in rat liver microsomes of pantoprazole enantiomers. Results The mean area under the curve value of S-pantoprazole was 1.5 times greater than that of R-pantoprazole after administration of racemic pantoprazole to rats (20 mg/kg, p.o.). There were significant differences in k_e (p < 0.05), t_1/2 (p < 0.01), and mean residence time (p < 0.01) values between the two enantiomers. In the in situ absorption study, the absorption rate constants were of no significant differences between the two enantiomers. The mean unbound fraction of R-pantoprazole was slightly greater than that of S-pantoprazole. The intrinsic clearance (CL_int) of the formation of the 5′-O-demethyl metabolite from S-pantoprazole was 4-fold lower than that from R-pantoprazole. However, the CL_int value for the sulfone and 6-hydroxy metabolites from S-pantoprazole was higher than that from R-pantoprazole. The sum of the CL_int of the formation of all three metabolites was 3.06 and 4.82 mL/min/mg protein for S- and R-pantoprazole, respectively. Conclusions This study suggests that the enantioselective pharmacokinetics of pantoprazole enantiomers in rats is probably ascribable to their enantioselective metabolism, which is contributed by all the three metabolic pathways, including sulfoxide oxidation, 4′-O-demethylation, and 6-hydroxylation.     

普罗帕酮两对映体间的药动学和药效学相互作用研究

采用随机、交叉、双盲法给予8名健康受试者多次剂量（150mg,q6h)来考察普罗帕酮三种片剂（消旋体、左旋体、右旋体）和安慰剂,立体选择性高效液相色谱法测定稳态时一个给药间隔（0－6h)的血浆中两对映体浓度,心电图同时记录PR、QRS和QTc间隙并测试最大运动心率HRmax及血压变化情况,TopFit软件拟合参数。结果表明,三种制剂的平均驻留时间MRT及峰时Tmax无差别。给予消旋体片剂后,右旋体的清除率C1明显低于左旋体（P＜0.05),单纯给予对映体时,右旋体的清除率则大于左旋体（P＜0.001)。左旋体的存在提高了右旋体的血浆浓度,增强了β-受体阻断作用。普罗帕酮在人体内消除存在立体选择性,且两对映体产生了药效学上的相互作用。临床应用消旋体可不作剂量调整,但对某些患者应慎重使用。     

茶多酚对兰索拉唑及其代谢产物在大鼠体内药动学的影响

目的:研究茶多酚对兰索拉唑及其代谢产物5-羟基兰索拉唑和兰索拉唑砜在大鼠体内药动学的影响.方法:16只SD雄性大鼠随机分为单独用药组和联合用药组,前14 d联合用药组灌胃给予茶多酚400 mg·kg-1,单独用药组灌胃给予等体积生理盐水,qd.第15天两组给予兰索拉唑8 mg·kg-1,给药后不同时间点采取血样,LC-MC/MS法测定兰索拉唑及其代谢产物血药浓度,用DAS2.0软件分析其药动学参数,以考察茶多酚对兰索拉唑代谢的影响.结果:茶多酚(400 mg·kg-1·d-1)显著降低兰索拉唑(8 mg·kg-1)的AUC(0-4)、Cmax和t1/2Z(P<0.05),显著升高5-羟基兰索拉唑与兰索拉唑的AUC(0-4)比值R1(P<0.05),但对兰索拉唑砜的药动学无显著影响(P>0.05).结论:茶多酚能够显著降低兰索拉唑在大鼠体内的口服生物利用度,其原因可能与茶多酚诱导CYP2C19有关.     

兰索拉唑片在人体内的药动学研究

目的 采用RP-HPLC法进行兰索拉唑的血药浓度检测和药动学研究.方法 采用Agilent C18色谱柱(250 mm×5mm,5μm),流动相为乙腈-1‰三乙胺水溶液(pH7) (30∶70),流速1.0 mL·min-1,进样量20 μL,内标为奥美拉唑.血浆样品经乙酸乙酯提取后,于285 nm处检测.结果 0.05～1.60 μg· mL-1兰索拉唑与峰面积比值的线性关系良好(r ＝0.9997),最低定量限为20 ng·mL-1(S/N ＞3),日内RSD＜ 7.94％(n＝5),日间RSD ＜9.41％(n＝5),提取回收率＞95.79％.结论 所用方法可用于临床上兰索拉唑片血药浓度的检测及药动学研究.     

Effect of Experimental Diabetes Mellitus and Arthritis on the Pharmacokinetics of Hydroxychloroquine Enantiomers in Rats

Purpose. To study the effect of experimental diabetes and arthritis on the pharmacokinetics of hydroxychloroquine (HCQ) enantiomers in rats. Methods. The pharmacokinetic studies were carried out following administration of 40 mg/kg of racemic HCQ to diabetic, insulin-treated diabetic, adjuvant arthritic and control rats. Results. Renal (70% and 62% for R- and S-HCQ, respectively) and non-renal clearance (100% and 145% for R- and S-HCQ, respectively) of HCQ enantiomers were significantly increased in diabetic rats. Diabetes-induced alterations in the disposition of HCQ were reversed by insulin treatment. In arthritic rats, systemic clearance (CL) of HCQ enantiomers was significantly reduced (1.05 ± 0.15 and 1.3 ± 0.19 1/h/kg for R- and S-HCQ, respectively) compared to controls (1.69 ± 0.32 and 1.93 ± 0.34 1/h/kg for R- and S-HCQ, respectively). The fraction unbound of the R- and S-HCQ were 49.4% and 50.5% lower in platelet rich plasma of arthritic rats compared to healthy rats. Increased blood concentrations of HCQ enantiomers in arthritic rats were significantly related to the degree of inflammation. Conclusions. Diabetes significantly increased the CL of both R- and S-HCQ by increasing renal and non-renal clearance. Arthritis caused a significant decrease in CL of HCQ enantiomers through increased binding and a decreased intrinsic clearance. The effect of the diseases on the pharmacokinetics of HCQ, however, was not stereoselective.This work was presented, in part, at the Ninth Annual Meeting of the American Association of Pharmaceutical Scientists,     

Pharmacokinetic and Pharmacoimmunodynamic Interactions Between Prednisolone and Sirolimus in Adrenalectomized Rats

Prednisolone (Pred) and sirolimus (SIR) are immunosuppressive compounds acting through different mechanisms with moderate synergism found in vitro. Both drugs are metabolized partly by CYP3A enzymes. After iv administration of placebo, Pred (5 mg/kg), SIR (1 mg/kg), or Pred with SIR (5 and 1 mg/kg doses) to adrenalectomized male rats, Pred plasma and SIR whole blood concentrations were followed for 48 hr along with circulating T-helper and T-cytotoxic cell counts. Ex vivo whole blood lymphocyte proliferation marked host responsiveness. An extended indirect PK/PD model was used to describe responses to these drugs, alone or combined. An interactive two-stage population analysis showed no modification in drug PK. Mean Pred plasma clearance was 0.655 L/hr (interrat variability: 11%) and significantly increased with weight. Mean SIR whole blood volume of distribution and clearance were 5.6 L (62%) and 0.28 L/hr (32%), and animal scaling showed weight ^power proportionality. In vitro metabolism studies showed no significant inhibition of Pred or prednisone CYP3A metabolism by SIR (50 M), but this pathway accounted for less than 5% of Pred metabolism. Pred decreased numbers of T-helper lymphocytes with a mean IC₅₀ of 37.8 nM (21%) alone or 12.3 nM (130%) with SIR. Results for T-cytotoxic lymphocytes were similar. SIR increased lymphocyte numbers with a mean IC₅₀ of 52.2 nM (24%) for T-helper and 28.8 nM (51%) for T-cytotoxic cells. Taking into account drug effects on lymphocyte trafficking, Pred directly inhibited ex vivo lymphocyte proliferation with a mean IC₅₀ of 1.08 nM (38%). SIR, after a transduction step, inhibited proliferation with a mean IC₅₀ of 1.00 nM (26%). Responses measured after drug coadministration were reasonably quantitated by addition of single drug effects. Since, at pharmacologic concentrations in rats, Pred and SIR did not interact in their PK but synergistically or additively interact in their dynamics, their joint therapeutic use is promising. The adrenalectomized rat may be a suitable animal model to characterize drug effects on lymphocyte trafficking and reactivity.     

葛根芩连汤中小檗碱在正常和糖尿病大鼠的药动学比较

目的：比较葛根芩连汤中小檗碱在糖尿病模型大鼠和正常大鼠的药动学行为差异。方法：采用腹腔注射链脲佐菌素诱发大鼠实验性糖尿病模型,与正常大鼠共同饲养6周后,灌胃给予葛根芩连汤,于给药后10,30rain,l,2,3,4,6,8,12,24h从眼底静脉丛取血,采用HPLC法测定血浆中小檗碱的浓度,以DAS软件拟合药动学参数。结果：小檗碱在正常大鼠和糖尿病模型大鼠中的cmax分别为（28．88±2．45）和（37．79±3．33）ng·ml-1（P〈0．05）,AUC0-24分别为（210．58±6．03）和（305．63±11．9）ng·h·ml-1（P〈0．05）。结论：糖尿病可能对小檗碱在体内的吸收、分布、代谢和排泄过程中一个或多个环节产生影响,提高了其体内生物利用度,有利于其治疗作用的发挥。     

Pharmacokinetics and Bioinversion of Ibuprofen Enantiomers in Humans

An open, randomized, six-way crossover study was conducted in 12 healthy males to assess pharmacokinetics and bioinversion of ibuprofen enantiomers. The mean plasma terminal half-life (t_1/2) of R(–)ibuprofen was 1.74 hr when intravenously infused as a racemic mixture and was 1.84 hr when intravenously infused alone. The mean t_1/2 of S( + )ibuprofen was 1.77 hr when dosed as S( + )ibuprofen. Examination of values of both the absorption and disposition parameters of R(–)ibuprofen revealed that the kinetics of R(–)ibuprofen were not altered by concurrent administration of S( + )ibuprofen. In this study, there was little or no presystemic inversion of R(–)ibuprofen to its S( + )isomer. Also, 69% of the intravenous dose of R(–)ibuprofen was systemically inverted and 57.6% of the oral dose of R(–)ibuprofen lysinate was bioavailable as S ( + )ibuprofen. These results indicate that the bioinversion of R(–)ibuprofen administered orally is mainly systemic. Because bioinversion of R(–)ibuprofen is not complete, S( + )ibuprofen produced higher bioavailability of S( + )ibuprofen (92.0%) than either racemic ibuprofen (70.7%) or R(–)ibuprofen (57.6%). However, bioavailability of R(–)ibuprofen (83.6%) when dosed alone was not significantly different from when dosed as racemic mixture (80.7%).     

Chiral-LC-MS/MS法同时测定人血浆中兰索拉唑对映体的浓度

目的:建立Chiral-LC-MS/MS法同时测定人血浆中S-兰索拉唑和R-兰索拉唑的浓度.方法:以乙腈作为蛋白质沉淀剂,对血浆中的兰索拉唑对映异构体进行Chiral-LC-MS/MS分析.色谱柱:Chiralpak IC柱(4.6 mm×150 mm,5μm),柱温为30℃,流动相为10 mmol·L-1醋酸铵(含0.05%醋酸)-乙腈(50:50,v/v),兰索拉唑对映异构体在9.0 min内可达到基线分离.采用AB QTRAP 5500质谱仪,使用电喷雾离子化(ESI)正离子模式,兰索拉唑和内标(埃索美拉唑)的多反应监测(MRM)扫描离子对分别为m/z 370.1→252.1和346.1→198.1.结果:该方法无明显的基质效应,S-兰索拉唑和R-兰索拉唑在标准曲线范围内线性关系良好,标准曲线的线性范围均为20.00~10000 ng·mL-1,准确度在±15%,批内和批间精密度均小于10%.在兰索拉唑对映体的储存、 处理和分析过程中没有发现两者间的手性转化,测定过程中各化合物稳定性符合要求.结论:建立了简单、高选择性的Chiral-LC-MS/MS方法,可用于同时测定人血浆中的兰索拉唑对映体的浓度.     

兰索拉唑在胃溃疡患者及健康人体内的药动学研究

目的:比较兰索拉唑在胃溃疡患者及健康人体内药动学行为的差异。方法:12名男性受试者(健康者和胃溃疡患者各6名),静脉滴注300mg·L-1兰索拉唑注射液250mL后于不同时间点取血并分离血浆,采用高效液相色谱-二极管阵列检测器(HPLC-DAD)法检测血浆中兰索拉唑的浓度,以DAS2.0软件计算药动学参数。结果:健康者与胃溃疡患者静脉给予兰索拉唑后,人体内药动学参数分别为:t1/(22.369±1.51)、(2.835±0.99)h,tma(x0.332±0.09)、(0.277±0.05)h,CL(19.882±8.19)、(14.460±7.79)L·h-1,cma(x1092.09±169.69)、(910.76±69.91)ng·mL-1,AUC0～6.(51475.98±590.23)、(2278.73±567.92)ng·h·mL-1,MRT0～6.(51.633±0.44)、(1.833±0.42)h。结论:兰索拉唑在胃溃疡患者体内的药动学过程较健康者发生了显著变化。     

兰索拉唑肠溶片健康人体药动学研究

目的:研究兰索拉唑肠溶片在人体内的药动学特点。方法:8名健康男性受试者单剂量口服30mg兰索拉唑肠溶片,血样加入内标(奥美拉唑)经预处理后用HPLC-UV法测定。结果:血浆中兰索拉唑浓度在20.00~2 000.00ng.mL-1范围内线性关系良好(r=0.999 9),日内、日间相对标准差均小于10%。主要药动学参数Cm ax为(876.14±278.11)ng.mL-1,tm ax为(3.81±0.70)h,t1/2为(1.68±0.70)h,AUC0~t为(2 925.04±1 110.88)ng.h.mL-1,AUC0~∞为(3 072.88±1 230.40)ng.h.mL-1。结论:本法操作简便,灵敏度高,无杂质峰干扰,测得的药动学参数可为其临床应用提供参考。     

The Effects of Danshen (Salvia miltiorrhiza) on Warfarin Pharmacodynamics and Pharmacokinetics of Warfarin Enantiomers in Rats

The effects of Danshen (Salvia miltiorrhiza), a popular traditional Chinese medicinal herb on the pharmacokinetics and pharmacodynamics of R- and S-warfarin stereoisomers were studied in rats. After a single oral dose of racemic warfarin (2 mg kg^?1), treatment with oral Danshen extract (5 g kg^?1, twice daily) for 3 days significantly altered the overall pharmacokinetics of both R- and S-warfarin and increased the plasma concentrations of both enantiomers over a period of 24 h and the prothrombin time over 2 days. At steady-state levels of racemic warfarin (0·2 mg kg^?1 day^?1 for 5 days) the 3-day treatment of Danshen extract (5 g kg^?1, twice daily) not only prolonged the prothrombin time but also increased the steady-state plasma concentrations of R- and S-warfarin. The results indicate that Danshen extracts can increase the absorption rate constant, area under plasma concentration-time curves, maximum concentrations and elimination half-lives, but decreases the clearances and apparent volume of distribution of both R- and S-warfarin. The pharmacokinetic and pharmacodynamic interactions of warfarin during co-treatment with Danshen extract observed in this study indicate an explanation for the clinically observed incidents of exaggerated warfarin adverse effects when traditional Chinese medicinal herbs or herbal products such as Danshen and Danggui (observed in a previous study) were co-administered.     

Similarities and Differences in Gastrointestinal Physiology Between Neonates and Adults: a Physiologically Based Pharmacokinetic Modeling Perspective

Physiologically based pharmacokinetic (PBPK) modeling holds great promise for anticipating the quantitative changes of pharmacokinetics in pediatric populations relative to adults, which has served as a useful tool in regulatory reviews. Although the availability of specialized software for PBPK modeling has facilitated the widespread applications of this approach in regulatory submissions, challenges in the implementation and interpretation of pediatric PBPK models remain great, for which controversies and knowledge gaps remain regarding neonatal development of the gastrointestinal tract. The commentary highlights the similarities and differences in the gastrointestinal pH and transit time between neonates and adults from a PBPK modeling prospective. Understanding the similarities and differences in these physiological parameters governing oral absorption would promote good practice in the use of pediatric PBPK modeling to assess oral exposure and pharmacokinetics in neonates.     

兰索拉唑片的人体药动学和生物等效性研究

目的建立HPLC测定人血浆中兰索拉唑浓度,评价兰索拉唑片（受试制剂）与兰索拉唑口崩片（参比制剂）的人体生物等效性。方法20名男性健康受试者采用双周期交叉试验,单剂量口服兰索拉唑片和口崩片各30mg,采集到的血浆样品加入奥美拉唑为内标,碱化后经乙醚-二氯甲烷提取,进行测定。色谱柱为ODS C18柱（150mm×4.6mm,5μm）;流动相：甲醇-乙腈-水（15∶28∶57）;检测波长：285nm,测定血浆中兰索拉唑浓度,应用DAS2.0.1软件计算主要药代动力学参数,并进行两种制剂的生物等效性评价。结果受试制剂与参比制剂的主要药代动力学参数：Tmax分别为（1.8±0.5）和（1.9±0.5）h;Cmax分别为（1144±240.8）和（1162±267.4）ng·mL^-1;t1/2分别为（1.4±0.3）和（1.4±0.3）h;AUC0～12分别为（3258±1222）和（3055±1151）ng·h·mL^-1;AUC0-∞分别为（3341±1251）和（3135±1182）ng·h·mL^-1,以AUC0～12计算,与参比制剂相比受试制剂兰索拉唑的相对生物利用度为（108.7±21.6）%（n=20）。结论两种兰索拉唑制剂具有生物等效性。     

Predicting Nonlinear Pharmacokinetics of Omeprazole Enantiomers and Racemic Drug Using Physiologically Based Pharmacokinetic Modeling and Simulation: Application to Predict Drug/Genetic Interactions

Purpose

The objective of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for each omeprazole enantiomer that accounts for nonlinear PK of the two enantiomers as well as omeprazole racemic drug.

Methods

By integrating in vitro, in silico and human PK data, we first developed PBPK models for each enantiomer. Simulation of racemic omeprazole PK was accomplished by combining enantiomer models that allow mutual drug interactions to occur.

Results

The established PBPK models for the first time satisfactorily predicted the nonlinear PK of esomeprazole, R-omeprazole and the racemic drug. The modeling exercises revealed that the strong time-dependent inhibition of CYP2C19 by esomeprazole greatly altered the R-omeprazole PK following administration of racemic omeprazole as in contrast to R-omeprazole given alone. When PBPK models incorporated both autoinhibition of each enantiomer and mutual interactions, the ratios between predicted and observed AUC following single and multiple dosing of omeprazole were 0.97 and 0.94, respectively.

Conclusions

PBPK models of omeprazole enantiomers and racemic drug were developed. These models can be utilized to assess CYP2C19-mediated drug and genetic interaction potential for omeprazole and esomeprazole.     

他汀类药物的药动学及与其他药物的相互作用

综述了他汀类药物的药动学性质及与其他药物的药动学相互作用。他汀类药物的单一疗法耐受性良好,不良反应发生率低,但与其他药物联用时,可能发生药动学相互作用,从而降低药物疗效或增强药物毒副作用。     

替加色罗大鼠体内药代动力学研究

目的 建立大鼠血浆中替加色罗的HPLC测定法,以测定大鼠ig替加色罗后的血药浓度,并对其药代动力学进行评价。方法 血浆样品加入内标后用乙酸乙酯提取,进行HPLC分析,流动相为甲醇-乙腈-水(60∶8∶32,含0.8%冰醋酸,0.4%三乙胺,v/v),流速为1.0ml/min,检测波长为310nm。大鼠ig5.0、10.0、20.0mg·kg^-1替加色罗后,测定其血浆中替加色罗的浓度,计算主要药动学参数。结果 血浆中替加色罗在2.00ng/ml～80.00ng/ml浓度范围内线性关系良好,血浆中替加色罗的最低检测限为1.0ng/ml。大鼠ig5.0、10.0、20.0mg·kg^-1替加色罗后,估算的末端相半衰期分别为0.86、1.09、1.08h,3种剂量的半衰期相近,AUC与剂量间呈良好的线性关系(r=0.9996)。结论 本实验建立的分析方法灵敏、准确、简便。在5.0～20.0mg·kg^-1剂量范围内,替加色罗在大鼠体内符合线性药物动力学特征,平均半衰期为1.01h。     

积雪草苷在大鼠体内的药动学研究

目的:研究积雪草苷在大鼠体内的药动学特点。方法:用高效液相色谱法,以葫芦素B为内标,甲醇为血浆蛋白沉淀剂,水-乙腈(24∶76)为流动相,测定一次性给大鼠尾静脉注射积雪草苷(42或126mg·kg-1)后SD大鼠血浆中积雪草苷的浓度。采用3p97程序计算药动学参数。结果:积雪草苷在SD大鼠体内的药动学符合二室开放模型,2个剂量组的t1/2α分别为1.89和1.73min,t1/2β分别为27.08和26.81min,K21分别为0.24和0.20min,K10分别为0.039和0.031min,K12分别为0.11和0.13min,AUC分别为1442.11和5749.78mg·min·L-1,CL分别为0.029和0.022mL·g-1·min-1,MRT分别为39.08和38.70min。结论:积雪草苷在SD大鼠体内的分布消除较快,呈一级动力学特征。     

兰索拉唑在正常及溃疡模型家兔体内药代动力学研究

目的:建立高效液相色谱法分析兔血浆中兰索拉唑的含量,并比较兰索拉唑在正常及溃疡模型家兔体内药代动力学行为的差异。方法:家兔于20℃水中浸泡8小时建立胃溃疡模型,耳缘静脉给予兰索拉唑注射剂后,分别在不同时间点收集血样,HPLC法测定,采用DASS2.0软件计算给药后的药物动力学参数。结果:兰索拉唑浓度在20~2000 ng.mL-1范围内线性关系良好,最低检测浓度为20 ng.mL-1。低、中、高3个浓度的提取回收率均大于85%,批内、批间相对标准差低于10%。与正常兔比较,溃疡模型家兔给予兰索拉唑药物后体内AUC(0-6.5)明显增加[(916.84±338.61)vs(522.72±172.16)μg.h.L-1,P<0.05]、体内平均滞留时间延长MRT(0-6.5)[(0.824±0.203)vs(0.69±0.13)h,P<0.05]、血浆消除半衰期增大[(0.88±0.44)vs(0.53±0.28)h,P<0.05]、血浆清除率显著减小[(2.74±1.70)vs(6.23±2.21)L.h-1,P<0.05]、最大血药浓度增大[(1091.31±348.94)vs(682.20±234.56)μ...     

木兰脂素在大鼠体内的药动学研究

目的:研究木兰脂素在大鼠体内的药动学特征。方法:采用高效液相色谱(HPLC)法。色谱柱为Kromasil C18,流动相为乙腈-四氢呋喃-水(39∶1∶60),流速为1.0 ml/min,检测波长为278 nm,柱温为35℃,进样量为20μl。8只Wistar大鼠于给药[10mg(生药)/kg]前及给药后0.25、0.5、0.75、1、1.5、2、4、8、12、20 h尾静脉断尾取血测定血药浓度,采用DAS2.1.1软件计算药动学参数。结果:木兰脂素检测质量浓度线性范围为0.05~10.00μg/ml(r=0.999 5),精密度、稳定性试验的RSD均小于13%(n=6),方法回收率为97.32%~102.15%(n=6),提取回收率为84.63%~90.02%(n=6)。木兰脂素在大鼠体内t1/2α为(0.48±0.22)h,t1/2β为(7.96±2.57)h,CL/F为(0.09±0.032)L/(h·kg),AUC0-20 h为(944.43±212.83)mg·h/L。结论:本方法精密度、稳定性、准确度均符合生物样品测定要求。木兰脂素在大鼠体内AUC0-20 h与剂量呈良好的线性关系,过程符合二室模型。