Pharmacokinetic and metabolic studies of high-dose busulphan in adults

Summary The pharmacokinetics of high-dose busulphan was studied in adult patients with acute myeloblastic leukaemia after oral doses of 1 mg·kg^–1 every 6 h for 4 days.The mean steady-state plasma concentration was 1080 ng/ml^–1 during the treatment. Individual steady-state concentrations after the last dose on average were 32% lower than those predicted from total AUC measurements following the first dose. Mean elimination half-life in plasma was 2.3 h after the last dose and 3.4 h after the first dose which suggests that busulfan may increase its own metabolic rate on repeated treatment.The cerebrospinal fluid/plasma concentration ratio of busulphan was 1.3. Busulphan showed insignificant protein binding in plasma (7.4%). About 2% of the dose was excreted unchanged in the urine.For the first time sulpholane, 3-hydroxysulpholane and tetrahydrothiophene 1-oxide were identified as urinary metabolites of busulphan in man.Presented in part at the European Bone Marrow Transplantation Meeting, Chamonix, France, April 9 to 13, 1988     

Pharmacokinetics of Methylergometrine (Methylergonovine) in the Rabbit and Man

Abstract: Methylergometrine concentrations in human and rabbit plasma were determined by a new radioimmunoassay after a single intravenous injection (0.2 mg in man and 0.05, 0.1 and 0.2 mg/kg in rabbits). Both in man and in the rabbit methylergometrine disappeared quickly from the plasma with a mean T_1/2β of 1.8 and 1.2–1.7 min. respectively. Similarly, the T_1/2/α-values were 32.1 and 27.3–93.2 min. The mean maximal response in the rabbit uterus in situ after 0.05, 0.1 and 0.2 mg/kg intravenously dose was found at 40 sec, 26 sec, and 26 sec. after the drug administration, respectively, and the dose response curve was quite steep. A significant correlation was found between the dose and response.     

钙拮抗剂尼卡地平的HPLC法分析及其在兔体内药代动力学研究

目的 :建立兔血浆中钙拮抗剂尼卡地平的反相高效液相色谱分析方法 ,并对其在兔体内的药代动力学进行研究。方法 :血浆样品在弱碱性条件下经环己烷 -异丙醇 (96∶4)提取 ,用LiChrosorbC18反相柱 ,甲醇 -水(75∶2 5 )为流动相 ,流速 1 0mL·min-1,检测波长 2 36nm等条件下 ,分析测定。结果 :方法平均回收率为98 2 7%～ 10 0 4% ,RSD <5 0 % ,线性范围 :11～ 110ng (r =0 9981) ,最低检测限为 10ng。 结论 :本法操作简便、准确灵敏、重现性好 ,可用于尼卡地平的药动学研究。     

肺炎支原体效价与疾病的关系

目的分析并探讨肺炎支原体抗体效价与儿童获得性肺炎的关系,研究其临床诊疗效果。方法选取我院于2010年7月至2011年12月期间收治的64例感染肺炎支原体的患儿,采用被动凝集法来动态检测这些患儿的肺炎支原体抗体效价,根据结果来分析肺炎支原体抗体效价和儿童获得性肺炎的关系。结果肺炎支原体抗体效价和儿童获得性肺炎的程度分组没有相关性,患儿的发病天数和肺炎支原体抗体效价间呈正相关。动态检测肺炎支原体抗体效价可以及时监测到患儿的病情变化。结论肺炎支原体抗体不能区别获得性肺炎是新近感染还是既往感染,但是不同时期检测肺炎支原体效价对于临床上获得性肺炎的诊断和治疗有重要意义。     

Effect of Alcoholic Beverages on the Pharmacokinetics of Doxycycline in Man

Abstract: In a randomized cross-over trial on six healthy medical students, alcohol (lg/kg) ingested as whisky did not modify significantly the absorption of 200 mg of doxycycline (DC) given in two tablets. Cheap red wine with a clear taste of acetic acid postponed the absorption of DC for 2–3 hours without affecting its 24-hour AUC or urinary excretion significantly. Another similar trial with other wines on 8 healthy students suggested that good regular wines do not retard DC absorption irrespective of their tannic acid content. However, acetic acid may postpone DC absorption by possibly slowing the rate of gastric emptying.     

氨苄青霉素合用氟美松对兔氨茶碱血药浓度及药代动力学的影响

目的：考察氨苄青霉素合用氟美松对氨茶碱血药浓度及动力学参数的影响.方法：取健康家兔10只,体质量2.5～3.4kg,肌肉注射氨茶碱,一次性给药18 mg/kg后,于耳缘静脉取血,7 d后进行氨茶碱与氨苄青霉素、氟美松合用实验.氨茶碱给药方式和剂量同单用时,氨苄青霉素为0.2g/kg耳缘静脉给药,氟美松为48 mg/kg耳缘静脉一次给药,给药后于耳缘静取血,采用高效液相色谱法（HPLC）测定茶碱血药浓度.结果：氨苄青霉素、氟美松与氨茶碱合用后,血药浓度（Co）,消除速率（Ke）增加,半衰期（t1/2）,体内清除率（CL）降低,分布容积[V（C）],平均驻留时间（MRT）增加,曲线下面积（AUC）变化不显著.结论：氨苄青霉素合用氟美松时,影响茶碱的正常代谢,注意调整氨茶碱的用量.     

毛细管电泳法测定冬虫夏草中核苷类的含量

目的 :探讨毛细管电泳法测定天然和人工冬虫夏草中腺苷、鸟苷和尿苷等核苷含量的可行性。方法 :采用BeckmanP ACESystem 5 0 10高效毛细管电泳仪 ,Beckman无涂层毛细管 (5 7cm× 75 μm ,有效长度 5 0cm) ,自动压力 (5 86kPa)进样6s ,检测波长 2 5 4nm ,电压 2 0kV ,温度 2 0℃ ,运行缓冲液为 0 2mol·L- 1 硼酸 (用 5mol·L- 1 氢氧化钠溶液调pH 8 5 )。进样前 ,毛细管分别以 1mol·L- 1 氢氧化钠溶液和运行缓冲液冲洗 5min。结果 :该法平均回收率腺苷为 97 0 % ,鸟苷为98 4% ,尿苷为 97 1% ;RSD分别为 0 72 % ,0 6 7% ,0 6 2 % (n =6 )。结论 :该法快速简便 ,灵敏度高 ,重现性好。     

HIV感染者中唐草片对洛匹那韦药动学的影响

目的 探讨唐草片对洛匹那韦在HIV感染者中的药动学的影响。方法 入组单纯服用含洛匹那韦的高效抗逆(反)转录病毒治疗方案的患者,达稳态后采血,然后联合服用唐草片2周后采血。采血时间点为：服用洛匹那韦前(0 h)、后0.5,1.0,2.0,3.0,4.0,6.0,8.0,10.0和12.0 h的样本,液相色谱串联质谱检测血浆中洛匹那韦浓度,并采用DAS 2.1.1软件计算药动学参数。结果 入组16例HIV感染者,单纯服用洛匹那韦组合者中的洛匹那韦AUC_0-t为(100.12±57.72)mg·L^-1·h^-1, C_max为(13.24±8.35)mg·L^-1,T_max为(4.16±2.39)h,T_1/2为(9.62±7.57)h;同时服用唐草片后,洛匹那韦的AUC_0-t为(95.55± 58.50)mg·L^-1·h^-1,C_max为(12.36±7.26)mg·L^-1,T_max为(4.06±3.06)h,T_1/2为(9.20±7.18)h。2组之间各参数均无显著差异。结论 唐草片对HIV感染者中洛匹那韦的药动学参数无影响。     

Effect of Uridine Diphosphoglucose on Levels of 5-Phosphoribosyl Pyrophosphate and Uridine Triphosphate in Murine Tissues

The purpose of the present investigation was to determine whether a single bolus intravenous injection (2000 mg/kg) of uridine diphosphoglucose (UDPG) could affect levels of PRPP in a transplanted mammary adenocarcinoma and in liver of CD8FI mice. Six hours following a single intravenous injection of UDPG, 2000 mg/kg, tumor PRPP was lowered to 80 pmol/mg protein, a 53% decrease compared to saline control tumors. Liver was more sensitive than tumor to the 5-phosphoribosyl pyrophosphate (PRPP)-depleting effects of a single bolus intravenous injection of UDPG, since significantly lower levels of PRPP were found in liver, but not in tumor, at doses of 500–1000 mg/kg of UDPG. Maximal depression (30% of saline control) or PRPP occurred in liver 6 hr after intravenous UDPG at 1000–2000 mg/kg. Enhanced levels of UDPG in plasma (half-life less than 10 min) and tumor was detected at 30 min after intravenous UDPG at 2000 mg/kg. There was no detectable increase in endogenous levels of UDPG in liver at this time, probably as a result of rapid metabolism of UDPG by liver. At this same time, a twofold increase in uridine triphosphate (UTP) was measured in liver after intravenously administered UDPG. In contrast, the level of UTP was not increased significantly above control values in tumor. These data suggest the potential use of UDPG to elevate UTP pools in normal tissues in the delayed rescue of cancer chemotherapeutic drugs such as 5-fluorouracil which function as a uridine analogue in these tissues.     

兔脑脊液中万古霉素LC-MS/MS测定方法的建立及其与冰片合用的药动学研究

目的 建立一种快速灵敏的LC-MS/MS用于兔脑脊液中万古霉素的测定,并进行万古霉素的药动学研究。方法 观察兔分别单独静脉注射万古霉素以及先灌胃给予冰片再静脉注射给予万古霉素后脑脊液中万古霉素的浓度变化。采用内标法进行定量分析,获得脑脊液中万古霉素的浓度,并采用DAS药动学软件拟合主要动力学参数AUC、C_max、T_1/2等。结果 脑脊液中万古霉素的批间精密度为4.7%~6.1%,批内精密度为1.4%~7.1%,准确度为93.6%~106.0%。万古霉素的线性范围为50~5 000 ng·mL^-1,标准曲线的相关系数r>0.99。合用冰片组兔脑脊液中万古霉素的AUC和C_max值明显高于单用万古霉素组。结论 该方法适用于万古霉素在兔脑脊液中的药动学研究。冰片可以提高万古霉素透过血脑屏障的能力。     

秦皮甲素、乙素在兔体内的药代动力学研究

根据β－环糊精与秦皮甲素乙素形成包含物，发生荧光增敏作用的原理，在适当的条件下，对兔血浆中的秦皮甲素乙素进行定时监测，绘制药时曲线，按照实用药代动力学的系列公式计算药代动力学参数，其几个主要药动学参数分别为：秦皮甲素的消除半衰期ｔ_１／２（β）为９．８１ｈ，吸收半衰期ｔ_１／２（ｋａ）为０．４５ ｈ，秦皮乙素的消除半衰期ｔ_１／２（β）为１２．２１ｈ吸收半衰期ｔ１／２（ｋａ）为０．３３ ｈ，曲线下面积秦皮甲素ＡＵＣ为１８．３３μｇ·ｈ·ｍＬ~－１，秦皮乙素ＡＵＣ为２７．１μｇ·ｈ·ｍＬ~－１，二者的吸收代谢虽不相同，但无显著差异．     

兔血浆中延胡索乙素药代动力学的研究

延胡索乙素是中药元胡中镇痛作用较强的有效成分，为了解药动学与药效学的关系，本文采用灵敏度高，选择性强的胶束荧光法。研究了延胡索乙素在兔血浆中的药代动力学，实验结果表明，延胡索乙素在兔体内的代谢属于吸收快，消除慢，能保持较长时间内有镇痛作用的药物，其几个主要药动学参数为ｔ１．２（α）为１．９８ｈ，ｔ１／２（β）为１６．７ｈ，ｔ１／２（ｋａ）为０．７２０ｈ，Ｋ２１为０．２３８ｈ＾－＾１，Ｋ１０为０．０     

Pharmacokinetic/Pharmacodynamic Evaluation of Deflazacort in Comparison to Methylprednisolone and Prednisolone

Purpose. The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone. Methods. Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes. Results. Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml · h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds. Conclusions. Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.     

聚乙二醇修饰对蛋白质类药物药代动力学的影响及相关的药动学研究方法

聚乙二醇（PEG）修饰在改善蛋白质类药物的理化性质的同时也会导致其体内药代动力学行为发生变化。而PEG修饰剂的分子大小、分子结构和修饰位点对蛋白质类药物的体内药代动力学行为和活性具有一定影响。根据有关文献报道,讨论这些影响因素,并介绍在对PEG修饰药物进行药代动力学研究时采用的新方法,如：群体药代动力学预测法及体内测定修饰物含量的电化学发光法和PEG特异性抗体法等。     

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.

     

米格列醇在人体内的药动学和生物等效性

目的:研究米格列醇在人体内的药动学特点和国产米格列醇片的生物等效性.方法:18名健康男性受试者,采用双周期交叉、自身对照试验设计,单剂量口服100 mg米格列醇,按照设定时间采集血样,预处理后的标本经LC-MS法进行检测.结果:经3P87拟合出米格列醇在人体内的主要药动学参数Ke为(0.36±0.06)h-1,Ka为(0.74±0.24)h-1,T1/2(a)为(1.03±0.33)h-1,T1/2(b)为(2.5±0.9)h,Tpeak为(2.4±0.6)h,Gmax为(1 883.9±912.4)μg·L-1,AUC为(7 592.7±4 207.4)μg·h·L-1,CL/f为(0.020±0.020)L·h-1,V/f为(0.06±0.07)L.方差分析结果表明,国产米格列醇片与法国产米格列醇片的主要药动学参数之间差异不明显.国产米格列醇的相对生物利用度为(97.1±13.5)%.结论:米格列醇在人体内的药动学特点符合一室模型,国产米格列醇与法国Sanofi Synthelabo公司生产的米格列醇是生物等效的.     

Effect of Probenecid on the Enantioselective Pharmacokinetics of Oxprenolol and Its Glucuronides in the Rabbit

Purpose. To study the effect of probenecid on the stereoselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit. Methods. An oral dose of 50 mg/kg racemic oxprenolol was given to nine rabbits twice, in random sequence with and without the concurrent administration of probenecid. Oxprenolol enantiomers were determined in plasma and urine by an enantioselective HPLC method. Oxprenolol glucuronides were measured in plasma and urine after enzymatic hydrolysis. Results. The disposition of the oxprenolol enantiomers in rabbits is stereoselective, mainly due to a difference in metabolism. Renal excretion is only a minor elimination route for unchanged oxprenolol, and the renal clearances of the enantiomers are similar. Pre-treatment with probenecid did not affect the plasma concentrations of the oxprenolol enantiomers, but there was a slight decrease in their urinary excretion. The plasma concentrations of the oxprenolol glucuronides are much higher than those of the parent enantiomers, and those of (S)-glucuronide are about twice those of its antipode. About 10% of the oxprenolol dose is excreted in the urine as glucuronides. The renal clearances of both glucuronides are similar, and markedly higher than the creatinine clearance. After probenecid, the mean glucuronide plasma levels were markedly higher, with for both glucuronides a more than twofold increase in mean AUC. Probenecid decreased the renal clearance of both glucuronides to about 30%. Moreover, it decreased slightly the formation clearance of (S)-glucuronide, while the formation clearance of (R)-glucuronide was not significantly influenced. Conclusions. Our results show that in the rabbit, both oxprenolol glucuronide diastereomers are actively secreted by the kidney, and that this process is inhibited by probenecid.