Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients

AIM: This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). METHODS: In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. RESULTS: After 2 weeks of SJW coadministration, dose-corrected AUC0-12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63-2.05)], 42%[1.72 (1.42-2.08)], and 41%[1.70 (1.17-2.47)], respectively. CSA doses were increased from a median of 2.7 mg day(-1) kg(-1) at baseline to 4.2 mg day(-1) kg(-1) at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20-51% and 43-90%, respectively. CONCLUSION: Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.     

单步萃取高效液相色谱法测定全血环孢素A浓度及在肝、肾移植患者中的应用

目的:建立一种简便可行的HPLC法测定肝、肾移植术后病人服用环孢素A(CsA)后的血药谷浓度.方法;病人血样经液-液一步提取后在C8柱上分析,流动相为甲醇:去离子水(75:25),检测波长为UV214nm.结果:线性范围50～800ng/ml,r=0.9998,平均回收率为105.4%.结论:本法具有简便、快速,普通实验室易于开展的优点,用于肝、肾移植术后po CsA的血药浓度监测,效果良好.     

The interaction of rifamycin SV with hepatic transport of taurocholic acid in the isolated perfused rat liver

Summary The effect of rifamycin SV on hepatic transport of taurocholic acid was investigated using isolated perfused rat liver technique. In all experiments, the perfused liver was maintained at taurocholic acid steady state by infusing constant amount of taurocholic acid.Infusion of rifamycin SV at various rates decreased biliary secretion of bile acids in a dose-dependent manner. Replacement of rifamycin SV by perfusion medium reversed this effect.To determine the site of action of rifamycin SV, kinetic experiments with ¹⁴C-taurocholic acid were undertaken. Rifamycin SV elevated the half-life of the medium disappearance of ¹⁴C-taurocholic acid. Furthermore, the antibiotic delayed the biliary appearance of ¹⁴C-taurocholic acid.The analysis of the results gave indications that the antibiotic interferred with hepatic uptake as well as biliary secretion of taurocholic acid.Part of this publication was presented in the 18. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft (1977)     

Effect of ponsinomycin on cyclosporin pharmacokinetics

Summary The influence of treatment with ponsinomycin, a new macrolide antibiotic, on the pharmacokinetics of cyclosporin A has been studied in 10 renal transplant patients. The pharmacokinetics of cyclosporin A was investigated at steady state, before and during treatment with ponsinomycin.On average, the blood levels of cyclosporin A were doubled by the macrolide, possibly due to a decrease in elimination or/and to an increase in absorption.Ponsinomycin should be use very carefully in patients treated with cyclosporin A.     

地中海拟无枝酸菌原生质体电融合及其在提高利福霉素SV发酵效价中的应用

对产利福霉素SV的地中海拟无枝酸菌 (Amycolatopsismediterranei)原生质体进行热灭活和紫外灭活标记 ,其热灭活条件为 5 2℃ ,1.5h ,紫外灭活条件为紫外线照射 ( 15W ,2 5cm ,2 70nm) 6 0min。将双灭活标记的原生质体用CRY 3型细胞融合仪进行电融合 ,得出 :成串电流频率 1.5MHz ,电压 5 8V ,成串时间 2 0s ,融合脉冲幅宽 80 μS ,融合电压 5 0 0V ,融合槽间距 0 .5mm时 ,融合率最高为 9.3× 10 -4 。对筛选的融合子产量试验表明 ,5 0 %以上的融合子产量高于出发菌株 ,有明显的正变作用 ,将融合子在利福霉素代谢类似物平板上分离纯化 ,获得了化学效价提高 30 %以上的产量稳定菌株。     

5 a以上肾移植患者环孢素血药浓度监测的临床分析

目的分析带肾存活5a以上肾移植患者环孢素（CsA）gn药浓度监测的临床意义。方法采用荧光偏振免疫法（mA）测定112例肾移植患者2530例次CsA血药浓度，并对其术后时间、性别、免疫抑制方案、CsA谷浓度（c0）、服药后2h血药浓度（c2）等进行统计分析。结果血药浓度随术后时间的延长而逐渐下降，且个体差异较大；男女2组血药浓度差异未见有明显统计学意义（P〉0.05）；2种免疫抑制方案中，CsA的用药剂量与血药浓度差异分别呈明显统计学意义（P〈0.05）。结论监测CsA血药浓度，可防止免疫过度、不足和药物毒性，从而提高移植肾的长期存活率。     

环孢素A血药浓度对肾移植术后患者血总胆固醇水平的影响

目的:研究接受肾移植手术后常规服用环孢素A(CsA)的患者其全血谷浓度C0及服药后2h的血药浓度C2对其总胆固醇水平是否有影响。方法:选择我院接受肾移植术病人其中28例,采用荧光偏振免疫分析法(FPIA)测定C0、C2,并按C0分为Ⅰ组:150~250μg.L-1,Ⅱ组:250~400μg.L-1;按C2进行分组,Ⅰ组:<1 000μg.L-1,Ⅱ组:1 000~1 300μg.L-1,Ⅲ组:>1 300μg.L-1。检测其术前及术后的血总胆固醇水平。结果:按C0,Ⅰ组C0(215.2±23.1)μg.L-1,总胆固醇升高(2.1±1.0)mmol.L-1,Ⅱ组C0(302.4±54.1)μg.L-1,总胆固醇升高(2.2±1.1)mmol.L-1,两组手术前后血总胆固醇水平均显著升高(P<0.01)。C0与血总胆固醇水平相关性分析,r=0.200(P>0.05);按C2,Ⅰ组C2(748.5±155.6)μg.L-1,总胆固醇升高(2.3±1.0)mmol.L-1,Ⅱ组C2(1131.6±71.3)μg.L-1,总胆固醇升高(2.0±1.2)mmol.L-1,Ⅲ组C2(1 578.2±376.0)μg.L-1,总胆固醇升高(2.3±0.5)mmol.L-1,3组手术前后血总胆固醇水平均显著升高(P<0.01)。C2与血总胆固醇水平相关性分析,r=0.237(P>0.05)。,结论:术后一个月,各组患者的总胆固醇均有明显增加(P<0.01),但这种改变用C0或C2分析均无明显相关性。     

大蒜注射液对肾移植患者环孢菌素A药动学的影响

目的观察大蒜注射液对肾移植患者环孢素A药动学参数的影响,以促进临床合理用药,提高人/肾存活率.方法分别对14例肾移植患者单用环孢素A与合用大蒜注射液后环孢素A的药动学参数进行研究和评价,采用荧光偏振免疫法测定不同时刻环孢素A在血中浓度,3P97程序拟合药动学参数,t'检验比较组间差异.结果单用组与合用组CsA药动学参数分别为,t1/2(ka)为1.15 h-1和1.06 h-1;t1/2(ke)为3.93 h-1和4.27 h-1;tmax为3.13 h-1和2.74 h-1;Cmax为480.1μg·L-1和365.6μg·L-1;两组各项药动学参数经统计分析处理差异无显著性(P＞0.05).结论大蒜注射液对肾移植患者环孢素A的药动学参数无影响,提示二者可以联合应用.     

高效液相色谱法测定人全血中环孢素A浓度

目的:建立正相高效液相色谱法(NP-HPLC)测定肾移植患者全血中环孢素A(CsA)的浓度.方法:患者全血经乙醚单步萃取后,以正己烷-无水乙醇-乙腈(88∶10∶2)为流动相,采用CN色谱柱分析,柱温为50℃,于210 nm波长处检测.结果:本方法在50～1 000μg·L-1范围内具有良好线性关系,平均回收率为101.06%,日内和日间RSD均小于5.2%.结论:本法简便、准确,适用于肾移植患者术后CsA的常规治疗药物监测.     

Evaluation of pharmacokinetic interaction between cyclosporin A and probucol in rats

Purpose. The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. Methods. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun® capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral® capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. Results. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun® (corn oil) and Neoral® (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral® (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol. Conclusion. The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.     

液相色谱-串联质谱法测定肾移植患者全血中环孢素A及其2种代谢物浓度

目的:建立液相色谱-串联质谱法(LC-MS/MS)测定肾移植患者体内环孢素A及其两个代谢物浓度。方法:全血样品用乙腈沉淀蛋白后直接进样分析,流动相为乙腈-10mmol.L-1甲酸铵溶液-甲酸(85∶15∶0.5,v/v/v),流速0.5mL.min-1,采用电喷雾离子化源,检测方式为正离子多离子反应监测(MRM)。血药浓度数据用Topfit2.0软件,按非室模型计算药动学参数。结果:对所建分析方法进行了较全面的验证,考察了环孢素A及其代谢物的药动学特征。环孢素A的主要药动学参数谷浓度C0为(74.0±25.9)μg.L-1,峰浓度Cmax为(566.2±170.3)μg.L-1,达峰时间tmax为(1.8±0.4)h,消除半衰期t1/2为(4.6±0.9)h,0~12h药时曲线下面积AUC0-12为(2 173.5±580.1)μg.h.L-1。结论:所建方法灵敏,重现性好,选择性强,样品处理简单,可用于环孢素A及其代谢物浓度的监测和药动学研究。     

肾移植受者环孢素血药浓度监测频度及其临床意义

目的:研究肾移植术后患者环抱素(CsA)血药浓度监测频度的临床意义。方法:对24例肾移植术后患者296次CsA血药浓度监测进行回顾性分析,分2组:规律组15例201次规律性监测;非规律组9例95次因各种原因不能定期监测。比较2组CsA血药浓度统计学变异系数(CV)的差异及排斥反应组与非排斥反应组CsA血药浓度CV的差异。结果:规律组CsA血药浓度CV小于非规律组(P<0.05);非排斥组CsA血药浓度CV小于排斥组(P<0.05)。结论:规律性CsA血药浓度比非规律性监测平稳;排斥反应的发生率与CsA血药浓度的CV呈正相关。     

Influence of Rifamycin SV on bile acid metabolism in rats

Summary Sodium cholate was infused with or without Rifamycin SV in rats in order to determine the site of interference of the drug on hepatic bile salt metabolism. Both compounds were administered at rates such as to saturate their respective maximal excretory capacities. When Rifamycin SV was given, bile acid uptake and excretion significantly decreased, with a significant reduction of the percent of conjugated bile salts in bile. Rifamycin SV neither modified bile flow nor affected the correlation between bile flow and bile salt excretion. These data suggest that the antibiotic interferes with the three main steps of hepatic bile acid metabolism. the cholestatic effect and the modification of biliary bile salt output produced by Ryfamycin SV in rats, could be of clinical relevance.Part of this work was presented in the Herbsttagung der Deutschen Pharmakologischen Gesellschaft (München 3–6 Sept. 1979)     

Lymphocyte-sensitivity to glucocorticoid correlates with the sensitivity to cyclosporin A and tacrolimus in chronic renal failure patients

AIMS: Association between lymphocyte-sensitivity to immunosuppressants in transplant recipients in vitro and clinical outcomes has been demonstrated. In general, renal transplant recipients are treated with a combination of immunosuppressants such as either glucocorticoid/cyclosporin A (CsA) or glucocorticoid/tacrolimus (FK506) but the pharmacological complementarity of these drugs is still controversial. We examined relationships between the lymphocyte-sensitivities to these immunosuppressants. METHODS: We examined lymphocyte-sensitivities to prednisolone (PSL), CsA, and FK506 in vitro in a total of 190 chronic renal failure (CRF) patients and 140 healthy subjects. The lymphocyte-sensitivity was evaluated from the IC50 value against mitogen-stimulated lymphocyte-blastogenesis in vitro. RESULTS: Statistically significant correlations of the IC50 values in CRF patients between the following pairs of drugs were observed: PSL and CsA (P<0.0001; n=129, r=0.419), PSL and FK506 (P<0.001; n=54, r=0. 441), and CsA and FK506 (P<0.0001; n=45, r=0.608).Similar correlations were also observed in lymphocytes from healthy subjects. The population of CRF patients who exhibited high IC50 values (low sensitivities) to PSL and FK506 was significantly larger than that of healthy subjects (P<0.05). CONCLUSIONS: Patients who showed low lymphocyte-sensitivity to either of the drugs also may exhibit low sensitivity to the others, and thus they may have a high risk of unsatisfactory outcome under combination therapy after renal transplantation. To overcome this risk, the selection of immunosuppressants is recommended to be restricted according to individual lymphocyte-sensitivities to these drugs in vitro, or alternatively, by addition of other drugs with different mechanisms for immunosuppression.