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101.
102.
法莫替丁肠溶片的血浓度测定及其在人体的药代动力学研究 总被引:3,自引:0,他引:3
目的研究法莫替丁的血药浓度测定方法,并应用其进行法莫替丁片剂的人体药代动力学研究。方法采用固相萃取—高效液相色谱(HPLC)紫外检测法测定法莫替丁的血药浓度。18名健康男性志愿者,单剂量口服40mg法莫替丁片剂,不同时间点取静脉血,由血药浓度数据计算各自的主要药代动力学参数。结果所建立的血药浓度测定法能满足药代动力学实验要求。单次服用40mg法莫替丁片剂的主要药代动力学参数血药浓度-时间曲线下面积(AUC)0→12、AUC0→∞、Cmax、Tmax、T1/2分别为(882±185)、(912±187)ng·ml-1·h-1、(171±33)ng/ml、(2.3±0.4)和(2.6±2.7)h。结论法莫替丁的血药浓度测定方法简单、可靠。所得的药代动力学参数与国内外文献报道相似。 相似文献
103.
T. Saito Z. J. Zhang Y. Manabe T. Ohtsubo H. Saito 《European archives of oto-rhino-laryngology》1997,254(6):281-286
The effect of sodium thiosulfate (STS) on the pharmacokinetics and ototoxicity of cisplatin (CDDP) was investigated in guinea
pigs. Animals received three intramuscular injections of 7.5 mg/kg CDDP separated by intervals of 5 days with or without STS
(1,000 mg/kg) administered intraperitoneally immediately and 1 h after each injection of CDDP or 3 and 6 h later. When administered
alone, CDDP caused total outer hair cell (OHC) loss in the basal and second turns of the cochlea. In the group administered
CDDP and STS, damage to the OHCs was mild when STS was given concurrently, but was severe when STS was given 3 and 6 h later.
Pharmacokinetics measured as free and total platinum (Pt) concentrations in plasma and total Pt concentration in perilymph
was not affected after administration of STS with CDDP. These results suggest that an inactive Pt-thiosulfate complex is formed
in plasma and is measured as a free Pt component which enters the perilymph via the blood-cochlear barrier. Two possible mechanisms
are proposed by which STS reduces ototoxicity: entry of CDDP into target cells such as OHCs and striai marginal cells or binding
to intracellular macromolecules of these cells is prevented. 相似文献
104.
6名健康妇女分别于上臂、臀部和腹部三部位经皮给予合LNG的透皮控释传递系统(TCDS)后,用放射免疫法测定LNG血清浓度,计算其主要药物动力学参数。结果表明:在TCDS用药期间,三部位的C(max)、T(max)及AUC(0~168h)基本接近,部位间无显著性差异(P>0.05);TCDS揭除后,AUC(168~204h)及消除相半衰期T(1/2)(Ke)均以腹部最大,臀部次之,上臂最小,在腹部与上臂间有显著性差异(P<0.05)。上述结果可归因于TCDS对LNG的控释和人体皮下脂肪的“贮库效应”。 相似文献
105.
Martin A. Graham Suresh Senan Hernani Robin Jr. Nils Eckhardt Dennis Lendrem Jeffery Hincks Dennis Greenslade Roy Rampling Stanley B. Kaye Reinhard von Roemeling Paul Workman 《Cancer chemotherapy and pharmacology》1997,40(1):1-10
Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug
free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination
with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were
investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold;
firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine,
and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic
studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD10 to the LD50. The AUC at the LD10 (2932 μg ml-1min) was used to determine a target AUC value of 1173 μg ml-1min (equivalent to 40% of the mouse LD10 AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every
3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m2) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration
of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a
PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD10 294 mg/m2, LD50 303 mg/m2). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic
ptosis and conjunctivitis were observed at doses of >300 mg/m2. The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma (t
1/2=36±0.65 min) occuring at the LD10 dose of 294 mg/m2. A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of
36–450 mg/m2. Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m2 and the MTD was 390 mg/m2 for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally
bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold
increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the
two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m2 (range 1035–1611 μg ml-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose
enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism
observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between
species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have
been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at
tolerable doses.
Received: 27 May 1996 / Accepted: 30 September 1996 相似文献
106.
Wayne L. Furman John H. Rodman Margaret E. Tonda Xiaolong Luo Bettye Arnold Neyssa Marina Leslie Garrison Roberta Hanna Charles B. Pratt William H. Meyer 《Cancer chemotherapy and pharmacology》1997,41(3):229-236
A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have
great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor
and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited,
and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels.
Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with
myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered
once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic
studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule
only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose
studied (1000 μg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing
doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77–1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase
63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were
<1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent
activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no
demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained
by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase
in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either
extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling
circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the
systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.
Received: 29 January 1997 / Accepted: 9 May 1997 相似文献
107.
Colleen J. Gilbert William P. Petros James Vredenburgh Atif Hussein Maureen Ross Peter Rubin Randy Fehdrau Colleen Cavanaugh Donald Berry Craig McKinstry William P. Peters 《Cancer chemotherapy and pharmacology》1998,42(6):497-503
Purpose: Both ondansetron and cyclophosphamide are thought to be metabolized by hepatic microsomal processes. The purpose of this
study was to evaluate the potential pharmacokinetic interactions between ondansetron and high-dose alkylating agent chemotherapy.
Methods: A total of 54 breast cancer patients receiving high-dose cyclophosphamide, cisplatin and carmustine were treated prospectively
in four sequential cohorts. Cohorts I and II received continuous infusions of both ondansetron and prochlorperazine, and cohorts
III and IV received a continuous infusion of ondansetron alone at the same doses. All patients received lorazepam every 4 h.
A group of 75 matched historical controls had received a continuous infusion of prochlorperazine with lorazepam. Pharmacokinetic
monitoring of each drug used in the high-dose chemotherapy regimen was conducted. Results: Median AUCs of cyclophosphamide in patients receiving ondansetron (73.6 mg/ml · min) were lower than those of the control
patients (88.3 mg/ml · min, n = 75, P = 0.0004), but the median cisplatin AUC was approximately 10% higher and no difference in the disposition of carmustine was
demonstrated. Patients treated with ondansetron displayed a higher frequency of headaches than the controls. The frequency
of achieving complete emetic control was greater in the ondansetron + prochlorperazine groups compared to the ondansetron
alone groups and was greater in both these groups than in the prochlorperazine alone group on the first day of therapy only.
Conclusion: Ondansetron altered the systemic exposure to cyclophosphamide when these agents were administered concomitantly. Ondansetron
did not substantially improve overall emetic control when used alone but may improve control in combination with prochlorperazine.
Future randomized studies are needed to delineate the effect of ondansetron on the disposition of the active cyclophosphamide
metabolites so that clinical implications can be addressed.
Received: 28 October 1997 / Accepted: 9 March 1998 相似文献
108.
Preclinical pharmacology of the natural product anticancer agent 10-hydroxycamptothecin, an inhibitor of topoisomerase I 总被引:18,自引:0,他引:18
Ruiwen Zhang Yufeng Li Qiuyin Cai Tiepu Liu He Sun Brandon Chambless 《Cancer chemotherapy and pharmacology》1998,41(4):257-267
Purpose: 10-Hydroxycamptothecin (HCPT) is an indole alkaloid isolated from a Chinese tree, Camptotheca acuminata, and has a wide spectrum of anticancer activity in vitro and in vivo mainly through inhibitory effects on topoisomerase I.
HCPT has been shown to be more potent and less toxic than camptothecin and has recently undergone clinical trials. To determine
how HCPT might be best used as an anticancer agent, preclinical studies of the pharmacokinetics, tissue distribution, metabolism
and elimination of HCPT in rats were undertaken. Methods: HCPT was administered to rats by i.v. bolus injection at doses of 1, 3, and 10 mg/kg body weight. HCPT (lactone and carboxylate)
and its metabolites in plasma, urine, feces, and various tissues were quantitated by reversed-phase HPLC. Pharmacokinetic
parameters were then estimated. Results: Following i.v. administration at doses of 3 or 10 mg/kg, the plasma concentration-time profile for lactone HCPT could be
best described by a three-compartment model, with terminal elimination half-lives of 140.4 and 428.6 min, respectively. A
two-compartment model was used to fit the plasma concentration-time curve at 1 mg/kg, with a terminal elimination half-life
of 30.5 min. Carboxylate HCPT had a longer half-life than the lactone form of HCPT. During the initial 6 h after dosing, urinary
excretion was the major route of elimination, and fecal excretion became the major route of elimination thereafter. HCPT was
widely distributed to various tissues including the enterohepatic system, kidney, and bone marrow. The lactone form of HCPT
was detectable in various tissues examined up to 72 h after dosing at all the three test doses. HCPT glucuronides were present
in plasma, urine, feces and various tissues. No significant toxicity was observed at doses of 1 or 3 mg/kg. Polyuria and hematuria
were observed only during the initial 3 h after dosing at 10 mg/kg. Conclusions: Prolonged elimination of HCPT in vivo may have a significant impact on its therapeutic effects. HCPT is metabolized to its
carboxylate form and glucuronides. Dose-dependent toxicity was observed with i.v. administration of HCPT. The results of this
study should be useful in the design of future human trials with this anticancer drug.
Received: 6 September 1996 / Accepted: 15 July 1997 相似文献
109.
Tomoko Ohtsu Hirofumi Fujii Hisashi Wakita Tadahiko Igarashi Kuniaki Itoh Shigeru Imoto Masahiro Kohagura Yasutsuna Sasaki 《Cancer chemotherapy and pharmacology》1998,42(1):1-8
The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA)
as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and
14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition,
multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured
by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day
1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax),
area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more
frequently in the high-dose group (P<0.01). Liver dysfunction (n=5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (<10 ng/ml) values on day 1. Phenobarbital,
dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations
were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present
we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view.
Received: 2 May 1997 / Accepted: 13 October 1997 相似文献
110.
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 (6 0∶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ig 5 0、10 0、2 0 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 0 0ng/ml~ 80 0 0ng/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ig 5 0、10 0、2 0 0mg·kg 1替加色罗后 ,估算的末端相半衰期分别为 0 86、1 0 9、1 0 8h ,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~ 2 0 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 0 1h。 相似文献