多西紫杉醇脂质体的制备及其在家兔体内的药代动力学

背景与目的:多西紫杉醇(Docetaxel,DOC)已在临床应用于非小细胞肺癌、乳腺癌、卵巢癌等的治疗,但其水溶性差,现临床使用的注射剂均采用吐温-80和13%乙醇溶液作为混合溶媒,静脉注射时常引发严重的过敏反应而限制了其临床使用.本课题研究DOC脂质体的制备方法,并考察用聚乙二醇2000(poly ethylene glycol-2000,PEG-2000)修饰前后的两种脂质体在家兔体内的药代动力学.方法:用薄膜蒸发法制备普通和PEG-2000修饰的DOC脂质体,测定其包封率、粒径和表面电位;静脉注射给药后,以地西泮为内标,采用固相萃取-高效液相色谱法测定血浆中药物含量;用3p87程序和SPSS13.0统计软件处理和分析数据,计算有关药代动力学参数.结果:制备的DOC脂质体包封率＞75%,平均粒径在150 nm左右.普通市售多西紫杉醇注射液(market docetaxel,M-DOC)和普通脂质体(docetaxel liposome,L-DOC)及PEG-2000修饰的长循环脂质体(PEG-2000-modified DOC long circulating liposome,PEG-DOC-LCL)的分布相半衰期分别为(0.17±0.04)、(0.31±0.11)和(0.32±0.06)h,消除相半衰期分别为(8.54±1.05)、(11.18±1.33)和(10.51±1.13)h,表观分布容积分别为(13.66±3.62)、(8.65±1.11)和(6.31±0.55)L,0～24 h曲线下面积分别为(13.45±2.44)、(22.83±3.57)和(29.31±5.96)mg·(h·L)-1,零时间至所有原形药物全部消除时间内的曲线下面积分别为(15.07±2.76)、(28.70±4.95)和(36.95±9.13)mg·(h·L)-1,清除率分别为(1.10±0.18)、(0.54±0.08)和(0.42±0.07)L/h.结论:薄膜分散法制备的DOC脂质体包封率较高,粒径较小;两种DOC脂质体均可不同程度地增加DOC的曲线下面积,降低表观分布容积和清除率,从而延长其在血液循环中的时间,并以用PEG修饰的DOC脂质体效果更好.     

抗肿瘤新药——Capecitabine

Ｃａｐｅｃｉｔａｂｉｎｅ（卡培他滨）是一种新的口服氟嘧啶类抗肿瘤药，具有选择性的抗肿瘤活性。近年来国外研究表明，Ｃａｐｅｃｉｔａｂｉｎｅ对于蒽环类、紫杉醇和（或）多种化疗药耐药的局部晚期或复发转移乳腺癌有较好的疗效。对正常组织损伤小，全身毒副作用轻，患者耐受良好，有较高的生活质量，用药经济、方便，是一种有前途的抗肿瘤药。     

盐酸帕洛诺司琼注射液在健康受试者体内的药代动力学研究

  目的  评价盐酸帕洛诺司琼注射液在健康受试者体内的药动学特征。  方法  31例健康受试者分成3组,单次静脉注射盐酸帕洛诺司琼剂量分别为0.125,0.25和0.5 mg。采用超高效液相-串联质谱法（UPLC-MS/MS）测定人血浆中帕洛诺司琼浓度,采用DAS 2.1药动学软件进行药动学参数的分析和计算。  结果  单剂量静脉注射0.125,0.25和0.5 mg的盐酸帕洛诺司琼注射液后,AUC_0~168h分别为（7.5±2.5）、（15.2±4.0）、（34.8±9.7）μg·h·mL-1;消除半衰期t_1/2分别为（27.2±9.5）、（27.2±6.5）、（31.4±5.6）h。AUC_0~168h与剂量呈正相关,相关系数为0.998。受试者在研究期间未发生重度以上不良事件。  结论  本研究建立的检测方法简单、快速、准确、灵敏度高,适合盐酸帕洛诺司琼人体药代动力学研究。单次静脉注射盐酸帕洛诺司琼后,受试者耐受良好。在0.125~0.5 mg剂量范围内,帕洛诺司琼在健康受试者体内表现为线性药动学特征。      

碳铂腹腔给药HPLC测定法及犬的药代动力学研究

应用高压液相色谱(HPLC)法对6只犬腹腔内灌注碳铂(30mg/kg),不同时间取腹腔液、门静脉、外周血测定总铂浓度。结果表明,4小时内腹腔浓度最高,峰值浓度及平均浓度分别为外周血浓度的139倍和64倍,门静脉浓度为外周血浓度的13.3倍和6.5倍.证明腹腔给药可大大提高腹腔、门静脉及肝脏浓度,减低到达体循环量。对有效地杀灭腹腔亚临床转移、门静脉癌栓、防治肝转移十分重要,并对控制术后复发、医源性转移颇有意义。     

注射用紫杉醇脂质体与紫杉醇注射液在肿瘤患者中的药动学比较

目的:建立人血浆中紫杉醇(paclitaxel,PTX)浓度的液相色谱-质谱(liquid chromatography-mass spectometry,LC-MS)检测方法,比较注射用紫杉醇脂质体(paclitaxelliposomeforinjection,L-PTX)和常规紫杉醇注射液(conventional paclitaxel injection,C-PTX)在肿瘤患者中的药动学特征。方法:采用随机、开放和对照的试验设计方案。试验分2组,每组各8例患者,分别静脉滴注175mg/m2L-PTX或C-PTX,并于静脉滴注过程中的1.5和3h及滴注结束后的0.25、0.5、1、2、4、8、12、24、36、48和72h采集受试者血样。LC-MS法测定血药浓度,应用DAS2.0软件计算药动学参数并进行比较。结果:患者单次静脉滴注175mg/m2L-PTX与C-PTX的主要药动学参数:血浆峰浓度(Cmax)分别为6455±2247和7400±1542μg/L;药物血浆浓度-时间曲线下面积(area under the plasma concentration-time curve,AUC0-∞)分别为14812±2846和21693±2657μg·h·L-1;血浆消除半衰期(t1/2z)分别为30.5±7.3和13.7±3.2h;表观分布容积(Vz)分别为526.8±112.1和162.9±49.1L/m2;血浆清除率(plasmaclearance,CLz)分别为12.3±2.7和8.2±1.0L·h-1·m-2。经统计学分析,2组的药动学参数差异有统计学意义(P<0.05)。结论:脂质体包裹后改变了PTX的体内药动学特性,与常规PTX相比,脂质体制剂在肿瘤患者体内的分布特性和消除情况有显著不同,具有更好的组织亲和性与缓释作用。     

大剂量甲氨蝶呤化疗的脑脊液药代动力学研究

Objective: To study the cerebrospinal fluid pharmacokinetics of intravenously administered high dose-methotrexate (HD-MTX) and provide a solid fundament for clinical practice. Methods: MTX at a high dose ranging from 1.0 to 3.0 g per course was intravenously administered to 30 patients with malignant tumors. Blood and CSF samples were consecutively collected up to 36 h after the initiation of infusion (6 h). MTX concentrations were measured by using a reversed phase high-performance liquid chromatography (RP-HPLC) assay. Results: CSF MTX concentrations were (1.65±1.52)×10^-6, (4.3±3.34)×10^-7, (1.46±1.10)×10^-7 and (3.19±4.38)×10^-8 mol/L, respectively, at 0, 6, 12 and 24 h post infusion, and became undetectable at 36 h post infusion. The concentration-time curve of CSF MTX closely resembled that of the plasma MTX and fitted with the following linear regression equation: Ŷ=0.057 97+0.010 82X (Ŷ: CSF MTX concentration, X: Plasma MTX concentration, r=0.8357). Conclusion: CSF MTX was metabolized in a linear two-compartment model. Additionally, pharmacokinetic analysis of MTX levels indicated a positive correlation between CSF MTX and plasma MTX levels.     

肿瘤患者单次和多次口服替吉奥片的药动学研究

目的：评价肿瘤患者单次和多次口服替吉奥片的药动学特征。方法： 设单次给药组10例, 给药剂量60 mg; 连续给药组9例, 每次给药剂量60 mg, 1日2次, 连续服用7 d。采用液相色谱-串联质谱法测定血浆中替加氟及其代谢物5-氟脲嘧啶（5-FU）、 吉美嘧啶 （CDHP） 和奥替拉西 （Oxo） 的浓度。采用DAS2.0药动学软件进行药动学参数的分析和计算。结果： 单次给药替加氟Cmax为 （1407±383）ng·mL-1,AUC0-t为 （15 403±8439） ng·h·mL-1, 活性代谢物5-氟脲嘧啶Cmax为 （128±36） ng·mL-1, AUC0-t为（539±138） ng· h· mL-1, 吉美嘧啶Cmax为 （222±93） ng· mL-1, AUC0-t为 （962±390） ng· h· mL-1, 奥替拉西Cmax为 （33.2±14.6） ng· mL-1, AUC0-t为 （117±64） ng·h·mL-1。与单次给药相比, 多次给药后替加氟的Cmax和AUC增加明显 （P<0.05）, 但其增加程度与理论蓄积系数接近, 而代谢物氟脲嘧啶、 吉美嘧啶及奥替拉西的Cmax和AUC无明显增加。受试者在研究期间未出现重度以上不良反应。结论： 口服替吉奥片后, 受试者耐受良好。多次给药后, 替吉奥片主要成分的药代动力学行为没有发生明显变化。     

氟尿嘧啶植入剂胃癌术后腹腔缓释化疗的药动学研究

目的探讨胃癌患者应用氟尿嘧啶植入剂进行腹腔缓释化疗的药动学规律。方法 26例胃癌参试者,切除肿瘤后分别于淋巴引流区域、瘤床等部位植入氟尿嘧啶植入剂,每点100 mg,共1000 mg。术后分别在规定的时间点抽取血样,测定5-FU的浓度,进行药动学模型拟合。结果胃癌患者氟尿嘧啶植入剂腹腔缓释化疗的体内的过程为一室缓释模型,药动学方程:Ct=A1e-Ket+A2e-Kat+A3e-Krt,外周血药达峰时间及峰浓度分别为141 h及0.22μg.ml-1,门静脉血药达峰时间及峰浓度分别为120 h及0.43μg.ml-1,外周血循环中消除、吸收及缓释半衰期分别为145 h、0.29 h及76.5h。结论此种腹腔化疗方法的药动学特点和参数,可为临床合理应用氟尿嘧啶植入剂,进行胃癌切除术后的区域性化疗提供参考数据。     

多柔比星药动学研究进展

文章主要就蒽环类抗肿瘤药物多柔比星新剂型、不同给药途径、不同给药时间和不同剂量下的药动学研究,以及多柔比星联合用药时、不同生理或病理条件的特殊群体的药动学研究现状进行综述。     

苯丁酸钠对BT325细胞的生长抑制和分化诱导

目的研究非毒性分化诱导剂苯了酸钠（phenylbutyrate,NaPB）在体外对人脑胶质细胞瘤BT325细胞的生长、分化的影响。方法应用形态学观察法、MTT分析法、流式细胞仪对在体外经不同浓度的NaPB处理过的BT325细胞进行检测。结果1．电子显微镜观察,在NaPB处理过的BT325细胞中,线粒体、内质网、弹力丝丰富,而在NaPB未处理的细胞中,有大量游离核糖体,上述细胞结构却未能观察到;2．NaPB在2mM时就能明显抑制BT325细胞的生长．并且有时间依赖关系及剂量依赖关系;3．应用流式细胞仪测定发现,经NaPB处理的细胞其S期在11．99％或13．17％．而未经处理的细胞其S期在20．17％。结论NaPB在体外不仅能够抑制人脑胶质细胞瘤的生长,而且能诱导细胞的分化,为NaPB分化治疗胶质瘤提供了实验依据。     

The pharmacokinetics of epirubicin and docetaxel in combination in rats

Purpose: The aim of the present study was to investigate possible pharmacokinetic interactions between epirubicin (EPI) and docetaxel (DTX) in rats. Methods: Male Sprague Dawley rats (n = 36) were used in the study. They received either DTX (5 mg/kg, n = 9), EPI (3.5 mg/kg, n = 13), or a combination (5 mg/kg + 3.5 mg/kg, n = 14), administered as intravenous bolus doses. Blood samples were collected at various time-points between 3 min and 45 h after dose administration. DTX and EPI plasma concentrations were determined by HPLC analysis. Pharmacokinetic evaluation was carried out using the NONMEM program. Results: A three-compartment model best described the concentration-time profiles for EPI. Clearance (CL), intercompartmental clearances (Q2 and Q3), central (V1) and peripheral (V2 and V3) volumes of distribution were estimated as 3.57 l/h per kg, 5.01 l/h per kg, 12.48 l/h per kg, 0.805 l/kg, 3.67 l/kg and 158 l/kg, respectively. A two-compartment model was sufficient to describe the DTX data. CL, intercompartmental clearance (Q), V1 and V2 for DTX were estimated as 7.3 l/h per kg, 4.6 l/h per kg, 0.69 l/kg and 2.6 l/kg, respectively. No significant change in the disposition of either drug was found when they were administered in combination compared to when they were given singly. Conclusion: Concurrent treatment with EPI and DTX does not appear to cause any changes in the pharmacokinetics of the drugs in rats. Received: 3 December 1998 / Accepted: 7 April 1999     

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.     

Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats

Purpose: To define the plasma concentrations of butyrate achieved and the profile of plasma butyrate concentrations versus time in mice and rats treated with tributyrin or sodium butyrate. Methods: Female CD₂F₁ mice were treated with tributyrin by oral gavage or with sodium butyrate by i.v. bolus or oral gavage. Oral tributyrin doses delivered to mice were 3.1, 5.2, 7.8, and 10.3 g/kg. Intravenous sodium butyrate doses were 0.31, 0.62, 0.94, and 1.25 g/kg. Oral sodium butyrate was given to mice at 5 g/kg. Subsequently, similar studies were performed in female Sprague-Dawley rats. Rats were given tributyrin by oral gavage at doses of 3.6, 5.2, or 10.3 g/kg or sodium butyrate i.v. at a dose of 500 mg/kg. Plasma butyrate concentrations were determined by gas chromatography. Results: In mice, oral dosing with tributyrin resulted in detectable plasma butyrate concentrations as early as at 5 min after treatment and produced peak plasma butyrate concentrations at between 15 and 60 min after dosing. Peak plasma butyrate concentrations increased proportionally with increasing tributyrin dose, but as the oral tributyrin dose increased there was a greater than proportional increase in the area under the curve of plasma butyrate concentrations versus time (AUC). At a tributyrin dose of 10.3 g/kg, plasma butyrate concentrations peaked at approximately 1.75 mM and remained ≥1 mM for between 10 and 60 min after dosing. However, approximately 10% of mice treated with this dose died acutely. At a tributyrin dose of 7.8 g/kg, plasma butyrate concentrations reached approximately 1 mM by 15 min after dosing and remained between 0.8 and 1 mM until 60 min after dosing. No mouse treated with this dose died acutely. Mice given tributyrin doses of 5.2 and 3.1 g/kg achieved peak plasma butyrate concentrations of approximately 0.9 and 0.5 mM, respectively, by 45 min after dosing. Plasma butyrate concentrations in these mice remained above 0.1 mM until 120 and 90 min after dosing, respectively. The four i.v. doses of sodium butyrate resulted in plasma concentration-time profiles that also indicated nonlinear pharmacokinetics and were well described by a one-compartment model with saturable elimination. Values recorded for the Michaelis-Menten constant (K _m) and the maximal velocity of the process (V_max) ranged between 1.02 and 5.65 mM and 0.60 and 1.82 mmol/min, respectively. Values noted for the volume of the central compartment (V_c) varied between 0.48 and 0.72 l/kg. At 1.25 g/kg, i.v. sodium butyrate produced peak plasma butyrate concentrations of 10.5–17.7 mM, and plasma butyrate concentrations remained above 1 mM for 20–30 min. Sodium butyrate delivered orally to mice at 5 g/kg produced peak plasma butyrate concentrations of approximately 9 mM at 15 min after dosing and plasma butyrate concentrations exceeding 1 mM for 90 min after dosing. In rats the 10.3-g/kg oral dose of tributyrin produced peak plasma butyrate concentrations of approximately 3 mM by 75 min after dosing and butyrate concentrations excedding 1 mM from 30 to 90 min after dosing. The plasma butyrate concentrations produced in rats by 5.2- and 3.6-g/kg doses were appropriately lower than those produced by the 10.3-g/kg dose, and there was no evidence of nonlinearity. The 500-mg/kg i.v. dose of sodium butyrate produced peak plasma butyrate concentrations in rats of approximately 11 mM, and the decline in plasma butyrate concentrations with time after dosing was consistent with saturable clearance. Conclusion: These studies document the ability to use oral administration of tributyrin to achieve pharmacologically relevant concentrations of butyrate in rodent plasma. They also document the nonlinear nature of butyrate clearance. These data are being used in the design of clinical trials of oral tributyrin in patients with malignancies and hemoglobinopathies. Received: 27 July 1998 / Accepted: 3 November 1998     

Nonlinear pharmacokinetics of CPT-11 in rats

The pharmacokinetics of a new water-soluble derivative of camptothecin. 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), and its major metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), was investigated after i.v. administration of 1 to 40 mg/kg of CPT-11 to rats. The plasma concentration of CPT-11 decreased biexponentially. The area under the concentration-time curve increased nonlinearly as the dose increased. SN-38 was found in the plasma, bile, urine, and feces. The SN-38 level was maintained at 0.06 to 0.08 micrograms/ml for 0.5 to 5.5 h depending on the dose, followed by exponential decay. Thirty-three to 58% of the CPT-11 was excreted without metabolism into the bile and urine for 24 h. SN-38 was mainly excreted into the bile. Analysis of the clearance has shown nonlinear pharmacokinetics which was due to metabolic processes such as the conversion of CPT-11 to SN-38.     

Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia.

Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID(50), 1-2 mM). Higher doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusion repeated every 28 days in a Phase I dose escalation study. The maximum tolerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversible neurocortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; median steady-state plasma concentration at this dose was 0.29 +/- 0.16 mM. Although no patients achieved complete or partial remission, four patients achieved hematological improvement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets and decrements in circulating blasts. Monitoring of the percentage of clonal cells using centromere fluorescence in situ hybridization over the course of PB administration showed that hematopoiesis remained clonal. Hematological response was often associated with increases in both colony-forming units-granulocyte-macrophage and leukemic colony-forming units. PB administration was also associated with increases in fetal erythrocytes. These data document the safety of continuous infusion PB and provide preliminary evidence of clinical activity in patients with myeloid malignancies.     

A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule.

PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.     

The pharmacokinetics of the quinazoline antifolate ICID 1694 in mice and rats

Summary N-(5-[N-(3,4-Dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-l-glutamic acid (ICI D1694) is an analogue of the thymidylate synthase inhibitorN ¹⁰-propargyl-5,8-dideazafolic acid (CB3717). CB3717 was found to be an active anticancer agent in early clinical studies, but its use was limited by its relative insolubility at physiological pH. ICI D1694 has been shown to be a more active anticancer agent than CB 3717 in model systems, and it is devoid of the acute renal toxicity associated with the administration of the latter drug to mice. In the present study, the pharmacokinetics of ICI D1694 were studied in both mice and rats using reverse-phase HPLC. In rats, ICI D1694 clearance (CL) conformed to a two-compartment open model and was rapid (CL=10.7 ml min^–1 kg^–1,t1/2=30 min). Excretion was mainly biliary (65% of the delivered dose in 4 h vs 12% in urine) in the rat following a 100-mg/kg i.v. bolus. A high degree of protein binding was seen in rat plasma (90% over the range of 20–100 m). In mice, ICI D1694CL=27 ml min^–1 kg^–1 andt1/2=30 min following 100 mg/kg i.v., which was significantly faster than CB3717 clearance (CL=6 ml min^–1 kg^–1,t1/2=93 min). ICI D1694 was fully bioavailable following i.p. administration (AUC=3.73 mg ml^–1 min i.v. 4.03 mg ml^–1 min i.p.), but its bioavailability following oral administration appeared to be low (approximately 10%–20%). Tissue distribution and excretion studies in mice suggested that biliary excretion predominated, confirming the results obtained in rats. Following an i.v. dose of 500 mg/kg ICI D1694 in mice, drug was detectable at 24h, suggesting the presence of a third phase of plasma clearance. The initial HPLC assay could not detect this third phase following a dose of 100 mg/kg; hence, a more sensitive assay was developed that includes a solid-phase extraction step. The latter assay was used to define the third phase of ICI D1694 clearance in mice, and preliminary studies demonstrated a terminal half-life of 6.5±2.7 h.These studies were supported by the UK Cancer Research Campaign and the British Technology Group     

A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.

PURPOSE: Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration. EXPERIMENTAL DESIGN: Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected. RESULTS: The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug. CONCLUSIONS: PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.     

Alterations in plasma pharmacokinetics of cisplatin in tumor-bearing rats

Summary Rats were inoculated s.c. with the Walker 256 solid carcinosarcoma, and when tumors reached a weight of approximately 2–3 g, pharmacokinetics, tissue distribution, and urinary excretion of ^195mPt-labelled cisplatin were studied. Cisplatin was given i.v., blood was sampled through arterial cannulae, and data were fitted to a three-compartment model. Distribution half-times were prolonged two- to threefold in tumor-bearing animals, although there was no change in elimination half-time. Initial and steady-state volumes of distribution were also increased in tumor-bearing animals. There was no change in AUC, urinary excretion, tissue distribution, or plasma protein binding. The results indicate that a solid tumor represents an additional compartment for distribution of cisplatin and alters the rate at which cisplatin is distributed from the plasma.