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1.
Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study 总被引:1,自引:0,他引:1
Carlo M. Camaggi Elena Strocchi Patrizia Carisi Andrea Martoni Alessandra Tononi Monica Guaraldi Margherita Strolin-Benedetti Constantin Efthymiopoulos Franco Pannuti 《Cancer chemotherapy and pharmacology》1992,30(4):307-316
The pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30-35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, less than or equal to 60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2-12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was less than 60 ml/min [group N, 122.8 +/- 44.0 l/h; group L, 104.4 +/- 27.7 l/h (P = 0.58) vs group R, 83.4 +/- 18.3 l/h (P = 0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6 +/- 10.8 h; group L, 69.9 +/- 10.2 h (P = 0.27) vs group R, 83.2 +/- 10.9 h (P = 0.025) and t1/2 gamma: group N, 41.3 +/- 10.1 h; group L, 47.0 +/- 7.4 h (P = 0.31) vs group R, 55.8 +/- 8.2 h (P = 0.025)]. After oral treatment, drug absorption occurred during in the first 2-4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4-18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1-21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
2.
Borner MM Schoffski P de Wit R Caponigro F Comella G Sulkes A Greim G Peters GJ van der Born K Wanders J de Boer RF Martin C Fumoleau P 《European journal of cancer (Oxford, England : 1990)》2002,38(3):349-358
The aim of this study was to determine the patient's preference for oral UFT/leucovorin (LV) or intravenous (i.v.) 5-fluorouracil (5-FU)/LV chemotherapy in metastatic colorectal cancer and to compare 5-FU exposure with these two treatment options. A total of 37 previously untreated patients with advanced colorectal cancer were randomised to start treatment with either oral UFT 300 mg/m2/day plus oral LV 90 mg/day for 28 days every 5 weeks or i.v. 5-FU 425 mg/m2/day plus LV 20 mg/m2/day for 5 days every 4 weeks. For the second treatment cycle, patients were crossed-over to the alternative treatment regimen. Prior to the first and after the second therapy cycle, patients were required to complete a therapy preference questionnaire (TPQ). The pharmacokinetics of 5-FU were determined by taking blood samples on days 8, 15 or 22 and 28 for UFT and on days 1 and 5 for i.v. 5-FU. 36 patients were eligible. 84% of the patients preferred oral UFT over i.v. 5-FU. After having experienced both treatment modalities, patients indicated taking the medication at home, less stomatitis and diarrhoea, and pill over injection as the most important reasons for their preference. The area under the plasma concentration curve (AUC) for 5-FU after UFT administration was 113 microM x min on day 8, 114 on day 15 and 98 on day 28; the peak levels (Cmax) were 1.2, 1.3 and 1.0 microM, respectively. The AUC for the 5-FU/LV courses was 3083 microM x min for day 1 and 3809 for day 5 (P=0.002). The Cmax was 170.1 and 196.2 microM (P=0.06) and the clearance 2.6 and 1.9 l/min, respectively (P=0.002). Patients with metastatic colorectal cancer clearly preferred oral over i.v. chemotherapy treatment. This choice was most importantly influenced by convenience and toxicity considerations. Although i.v. bolus 5-FU leads to higher peak 5-FU concentrations and AUC values compared with oral UFT, this pharmacokinetic advantage of i.v. 5-FU seems to translate mainly into higher toxicity as seen in large randomised studies comparing oral UFT/LV with i.v. 5-FU/LV. Oral UFT/LV compares favourably with i.v. 5-FU/LV in terms of toxicity and patient's preference and leads to prolonged 5-FU exposure, which is comparable to continuous i.v. 5-FU treatment. 相似文献
3.
Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration 总被引:2,自引:0,他引:2
The clinical formulation of leucovorin calcium (leucovorin, LV) is a mixture of stereoisomers [(6R,S)-5-formyltetrahydrofolate], which have been shown to differ significantly in plasma clearance and route of elimination after intravenous administration; the (6S) isomer is rapidly converted to 5-CH3 tetrahydrofolate (5-CH3 THF), and the (6R) isomer is slowly eliminated by renal excretion. The relative importance of (6S) LV and 5-CH3 THF in expanding reduced folate pools in tumor cells is unknown, but it is known that high concentrations of (6R) LV can support growth of folate-depleted cells and thus have the potential to interfere with the biological activity of the (6S) isomer. To examine the pharmacokinetics of the LV isomers and metabolites, we administered 1,000 mg of LV to five normal subjects as a 2-hour intravenous infusion and in divided oral 100-mg doses given over 24 hours. Plasma and urine samples were analyzed by reverse phase followed by chiral high-performance liquid chromatography. Following intravenous administration, peak plasma concentrations of (6R) LV, (6S) LV, and 5-CH3 THF were 148 +/- 32, 59.1 +/- 22, and 17.8 +/- 17 microM, respectively. During oral administration of LV, virtually no (6S) LV appeared in the plasma. Steady-state plasma concentrations of (6R) LV and 5-CH3 THF were approximately 1.5 +/- 0.23 and 2.8 +/- 0.41 microM, respectively. Intravenous administration of LV resulted in an area under the curve (AUC) for (6R) LV that was more than four times that of the biologically active (6S) folates, whereas oral administration produced an AUC for (6S) reduced folates [(6S) LV and 5-CH3 THF] that was approximately twice that of (6R) LV. After administration of high doses of LV intravenously, conversion of (6S) LV to 5-CH3 THF was saturable, as indicated by the prolonged (6S) LV half-life of 58 minutes and the slow (6S) LV clearance of 119.2 +/- 38 mL/min, compared with previously reported data for administration of low doses. This study illustrates that intravenous administration of LV produces equivalent AUCs of (6S) LV and 5-CH3 THF but a substantially higher AUC for (6R) LV. Oral administration over 24 hours results in an AUC of 5-CH3 THF equivalent to that obtained after intravenous dosing in the presence of only small amounts of (6R) LV. The optimal route of LV administration will ultimately be determined by ongoing studies of the cellular pharmacology of LV that will determine if high concentrations of (6R) LV interfere with the biological activity of the (6S) reduced folates. 相似文献
4.
Stapleton SL Reid JM Thompson PA Ames MM McGovern RM McGuffey L Nuchtern J Dauser R Blaney SM 《Cancer chemotherapy and pharmacology》2007,59(4):461-466
Purpose Pemetrexed, a multi-targeted antifolate that disrupts synthesis of both purines and pyrimidines, is approved for use in malignant
pleural mesothelioma and non-small cell lung cancer. Pemetrexed is currently being evaluated for anti-tumor activity in a
variety of solid and central nervous system tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of
pemetrexed in a non-human primate model that is highly predictive of human CSF penetration.
Methods Pemetrexed, 20 mg/kg (400 mg/m2), was administered intravenously to four non-human primates. Serial blood samples were obtained from all animals and serial
CSF samples were obtained from three animals. Plasma and CSF concentrations of pemetrexed were measured using LC/MS/MS and
the resulting concentration versus time data were evaluated using model independent and dependent methods.
Results Pemetrexed disappearance from plasma was best described by a two compartment model with a mean distribution half-life of 13.8 ± 3.2 min
and an elimination half-life of 70.0 ± 16.0 min. The volume of distribution of and the clearance from the central compartment
were 0.066 ± 0.017 l/kg and 3.6 ± 0.6 ml/min/kg, respectively. Peak CSF concentrations occurred 40–71 min after the start
of the infusion with an average of 0.26 ± 0.15 μM.
Conclusion The CSF penetration of pemetrexed was less than 2% (range 0.33–1.58%), suggesting that it should be used in conjunction with
other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases. 相似文献
5.
Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates 总被引:3,自引:0,他引:3
Kerr JZ Berg SL Dauser R Nuchtern J Egorin MJ McGuffey L Aleksic A Blaney S 《Cancer chemotherapy and pharmacology》2001,47(5):411-414
PURPOSE: Gemcitabine (dFdC) is a difluorine-substituted deoxycytidine analogue that has demonstrated antitumor activity against both leukemias and solid tumors. Pharmacokinetic studies of gemcitabine have been performed in both adults and children but to date there have been no detailed studies of its penetration into cerebrospinal fluid (CSF). The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following i.v. administration. METHODS: Gemcitabine, 200 mg/kg, was administered i.v. over 45 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of gemcitabine and dFdU concentrations. Gemcitabine and dFdU concentrations were measured using high-performance liquid chromatography (HPLC) and modeled with model-dependent and model-independent methods. RESULTS: Plasma elimination was rapid with a mean t1/2 of 8 +/- 4 min (mean +/- SD) for gemcitabine and 83 +/- 8 min for dFdU. Gemcitabine total body clearance (ClTB) was 177 +/- 40 ml/min per kg and the Vdss was 5.5 +/- 1.0 l/kg. The maximum concentrations (Cmax) and areas under the time concentration curves (AUC) for gemcitabine and dFdU in plasma were 194 +/- 64 microM and 63.8 +/- 14.6 microM.h, and 783 +/- 99 microM and 1725 +/- 186 microM.h, respectively. The peak CSF concentrations of gemcitabine and dFdU were 2.5 +/- 1.4 microM and 32 +/- 41 microM, respectively. The mean CSF:plasma ratio was 6.7% for gemcitabine and 23.8% for dFdU. CONCLUSIONS: There is only modest penetration of gemcitabine into the CSF after i.v. administration. The relatively low CSF exposure to gemcitabine after i.v. administration suggests that systemic administration of this agent is not optimal for the treatment of overt leptomeningeal disease. However, the clinical spectrum of antitumor activity and lack of neurotoxicity after systemic administration of gemcitabine make this agent an excellent candidate for further studies to assess the safety and feasibility of intrathecal administration. 相似文献
6.
L B Anthony M G Krozely N J Woodward J D Hainsworth K R Hande D E Brenner F A Greco T G Burish 《Journal of clinical oncology》1986,4(1):98-103
In a study of the antiemetic effectiveness of high-dose oral metoclopramide, 66 previously untreated patients receiving 60 mg/m2 cisplatin were entered into a double-blind randomized trial. Patients were stratified according to age and tumor type, then randomized to receive either oral or intravenous (IV) high-dose metoclopramide. Patients were evaluated for antiemetic protection, toxicity, affect (anxiety, hostility, and depression), and autonomic arousal (pulse rate and blood pressure) at three-hour intervals on the day of their chemotherapy. Metoclopramide serum levels were measured by high-performance liquid chromatography. Results indicated no significant differences between the oral and IV groups on any measurement of antiemetic protection, affect, or autonomic arousal. There were also no significant differences in side effects except for frequency of stools; patients who received oral metoclopramide had significantly more stools than patients who received IV metoclopramide. The mean (+/- SD) serum metoclopramide level at four hours achieved orally was 1,171 +/- 660 ng/mL; the mean (+/- SD) level achieved IV was 1,030 +/- 392 ng/mL (P = .498). We conclude that high-dose oral and IV regimens of metoclopramide as administered in this study have equivalent antiemetic efficacy in previously untreated patients receiving 60 mg/m2 cisplatin. 相似文献
7.
Renbarger J Aleksic A McGuffey L Dauser R Berg S Blaney S 《Cancer chemotherapy and pharmacology》2004,53(1):39-42
Purpose: SU5416 is a small, lipophilic synthetic molecule that selectively inhibits the tyrosine kinase activity of the VEGF receptor
Flk-1/KDR. The role of this agent in brain tumors is currently being investigated. Pharmacokinetic studies of SU5416 have
been performed in humans; however, there have been no studies of its penetration in the cerebrospinal fluid (CSF). We studied
the pharmacokinetics of SU5416 in plasma and CSF after intravenous (i.v.) administration using a nonhuman primate model that
is highly predictive of the CSF penetration in humans.Experimental design:SU5416 (85 mg/m2, about 3.8 mg/kg) was administered i.v. over 20 min to four nonhuman primates. Serial plasma and CSF samples were obtained
prior to, during, and after completion of the infusion, for determination of SU5416 concentrations. SU5416 was measured in
plasma and CSF using high-performance liquid chromatography (HPLC). Concentration-versus-time data were modeled using model-independent
and model-dependent methods.Results: Peak plasma concentrations ranged from 6.3 to 14.5 μM and the mean plasma AUC was 620±180 μM min. Disappearance of SU5416
from the plasma was best described by a one-compartment model with a half-life of 39±2.9 min. The volume of distribution was
36±11 l/m2 and the clerance was 0.62±0.2 l/min per m2. SU4516 was not quantifiable in the CSF.Conclusions: There is minimal penetration of SU5416 into the CSF after i.v. administration. The very low CNS exposure to SU5416 after
i.v. dosing suggests that this agent is not optimal for the treatment of leptomeningeal tumors.
Published online: 9 October 2003 相似文献
8.
Merrill J. Egorin Zhi-Min Yuan Dorothy L. Sentz Karen Plaisance Julie L. Eiseman 《Cancer chemotherapy and pharmacology》1999,43(6):445-453
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 (Vmax) 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 (Vc) 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 相似文献
9.
H B Muss F Richards D V Jackson M R Cooper D R White J J Stuart W Ramseur R M Christian H B Wells E Pope C L Spurr 《Cancer》1982,50(11):2269-2274
Eighty-one evaluable patients with recurrent or metastatic breast cancer were randomized to receive either vincristine 1 mg/m2, doxorubicin 40 mg/m2 on day one and cyclophosphamide 200 mg/m2 orally days 3-6 (VAC); or cyclophosphamide 350 mg/m2, methotrexate 20 mg/m2, and 5-fluorouracil 350 mg/m2 (CMF) intravenously, all on day 1. Courses of each of the above regimens were repeated every three weeks. Twenty-one of 45 patients (47%) on VAC and seven of 44 patients (16%) on CMF had complete or partial response (P less than 0.05). The duration of response was six months for CMF and nine months for VAC. Hematologic toxicity was minimal for both groups but three patients receiving VAC developed cardiac toxicity. Overall survival projections at this time indicate no differences between the VAC or CMF treated patients. 相似文献
10.
Jodi A. Muscal Patrick A. Thompson Vincent L. Giranda Brian D. Dayton Joy Bauch Terzah Horton Leticia McGuffey Jed G. Nuchtern Robert C. Dauser Brian W. Gibson Susan M. Blaney Jack M. Su 《Cancer chemotherapy and pharmacology》2010,65(3):419-425
Purpose
ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration.Methods
ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods.Results
The CSF penetration of ABT-888 was 57 ± 7% (mean ± SD). The peak ABT-888 concentration in the plasma was 0.62 ± 0.18 μM. Plasma and CSF AUC0–∞ were 3.7 ± 1.7 and 2.1 ± 0.8 μM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration.Conclusion
The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans. 相似文献11.
Stapleton SL Thompson PA Ou CN Berg SL McGuffey L Gibson B Blaney SM 《Cancer chemotherapy and pharmacology》2008,61(4):647-652
Purpose Valproic acid (VPA), a widely used antiepileptic, also inhibits histone deacetylase (HDAC), and is undergoing evaluation as
an anti-cancer agent. We studied the pharmacokinetics of VPA in the plasma and cerebrospinal fluid (CSF) in a non-human primate
model that is highly predictive of human CSF penetration to determine if levels of VPA required to inhibit HDAC in in vivo
models can be attained.
Methods Oral VPA, 75 mg/kg, was administered to four non-human primates. Serial samples of blood (n = 4) and CSF (n = 3) were obtained for pharmacokinetic studies of total and free VPA. Plasma and CSF VPA concentrations were measured using
the commercially available Abbott AxSYM VPA assay reagent system (Abbott Laboratories, Abbott Park, IL, USA). The resultant
plasma and CSF data were evaluated using pharmacokinetic modeling methods.
Results At a dose of 75 mg/kg, the maximum plasma concentration of VPA was 130.1 ± 70.6 μg/ml (mean ± standard deviation) for total
drug and 53.3 ± 44.4 μg/ml for free drug. The mean plasma area under the curve (AUC) for total drug was 680 ± 233 μg/ml h and for free drug 146 ± 89 μg/ml hr. The maximum CSF concentration occurred 2–3 h after administration and was 28.2 ± 18.6 μg/ml. The CSF AUC for VPA was 108 ± 52 μg/ml h. The CSF penetration of VPA was 12.9 ± 5.1% for total drug and 57.0 ± 8.7% for free drug. Disappearance from the plasma
followed non-linear kinetics with a V
max of 321.2 ± 65.6 μg/kg/min and a K
m of 17.2 ± 13.7 mg/l.
Conclusion Valproic acid deserves further study for the treatment of CNS tumors given its high CSF penetration after oral dosing coupled
with the anti-tumor activity observed in preclinical studies. 相似文献
12.
J de Jong G J Geijssen C N Munniksma J B Vermorken W J van der Vijgh 《Journal of clinical oncology》1992,10(12):1897-1906
PURPOSE: N-l-leucyldoxorubicin (Leu-Dox) was developed as a prodrug of doxorubicin (Dox) to circumvent the cardiotoxicity associated with repeated administration of Dox. Our purpose was to assess the pharmacokinetics of Leu-Dox, Dox, doxorubicinol (Dol) and four other metabolites for pharmacokinetically guided dose-escalation and to verify the prodrug character of Leu-Dox. PATIENTS AND METHODS: Blood and urine of 14 patients were sampled during the phase I clinical trial and analyzed by high-performance liquid chromatography. Dose levels of Leu-Dox ranged from 18 mg/m2 to 225 mg/m2, the maximum-tolerated dose (MTD). Hematologic parameters were monitored regularly in each patient. RESULTS: Leu-Dox was rapidly distributed (half-life at alpha phase [t1/2 alpha] = 2.5 +/- 0.6 minutes) followed by a biphasic elimination (half-life at beta phase [t1/2 beta] = 17.4 +/- 7.3 minutes; half-life at gamma phase [t1/2 gamma] = 1.5 +/- 0.5 hours), as measured over the first 12 hours after administration. In three patients, in whom Leu-Dox was found in the plasma for up to 48 hours after injection, a final elimination half-life (t1/2,elim) of 16 hours was observed. The t1/2,elim of Leu-Dox was short (0.6 to 16.5 hours) compared with the t1/2,elim of Dox (38 +/- 11 hours). The mean residence time and apparent volume of distribution were 23 +/- 5 minutes and 19 +/- 6 L/m2, respectively. Only 1.5% to 5% of the dose was excreted in the urine over 48 hours, with Dox as major constituent. Dox was rapidly formed, reaching its maximum concentration within 10 minutes after the end of Leu-Dox infusion. Areas under the plasma concentration versus time curve (AUC infinity, mean +/- SD, n = 16) of Leu-Dox, Dox, and Dol were 115 +/- 27 mumol.min/L, 41 +/- 12 mumol.min/L, and 33 +/- 14 mumol.min/L after a dose of 60 mg/m2 Leu-Dox (= 86 mumol/m2). After the same molar dose of Dox (50 mg/m2 = 86 mumol/m2), the AUC infinity of Dox was 179 mumol.min/L, indicating that Leu-Dox was converted into Dox for 23% in the plasma compartment. The AUCs infinity of Leu-Dox, Dox, and Dol increased linearly with the dose. Negligible AUCs were observed for the other four metabolites. The AUCs infinity of Leu-Dox and Dox at the MTD (517 and 145 mumol.min/L, respectively) were lower than those in mice at the LD10 (1,930 and 798 mumol.min/L, respectively), which means that the MTD could not be predicted from the preclinical pharmacokinetics in mice. Hematologic toxicity, especially the WBC count, appeared to correlate much better with the AUC of Dox (r = .91) than with the AUC of Leu-Dox (r = .74), thus confirming the prodrug character of Leu-Dox. CONCLUSIONS: Dox is rapidly formed from Leu-Dox, and seems causative in the observed myelotoxicity. The MTD could not be predicted from the AUC at the LD10 in mice. 相似文献
13.
Although intravenous (IV) 5-fluorouracil (5-FU) and uracil/futraful (UFT) have comparable antitumour efficacy in the treatment of metastatic colorectal cancer (MCC), we wanted to assess which of these two regimens would be preferred by our patients. We randomized 20 previously untreated patients with MCC at our centre to receive oral UFT or bolus IV 5-FU both associated with leucovorin. After the first cycle patients were crossed over to the other arm. Before the third cycle we left patients to choose one of the regimens to continue their treatment until disease progression. Two patients chose 5-FU and 18 chose UFT (P < 0.001). Fewer side effects (50%) and convenience of home treatment (40%) were the main reasons for their choice for the oral regimen. UFT induced less mucositis (P = 0. 02) and diarrhoea (P = 0. 01). We conclude that convenience and lower toxicity may explain the observed preference for oral UFT. 相似文献
14.
A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer 总被引:1,自引:0,他引:1
P F Conte M Bruzzone S Chiara M R Sertoli M G Daga A Rubagotti A Conio M Ruvolo R Rosso L Santi 《Journal of clinical oncology》1986,4(6):965-971
After primary surgery, 125 patients with epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] 1c + IIb + IIc = 22 patients, FIGO III = 82 patients, FIGO IV = 21 patients) were randomly allocated to receive PC (cisplatin 50 mg/m2 + cyclophosphamide 600 mg/m2 on day 1 every 28 days) (corrected) or PAC (PC + doxorubicin 45 mg/m2). After six cycles, patients clinically disease-free or with resectable residual disease were submitted to second-look surgery. After restaging, patients in surgical complete response (CR) stopped treatment while those responding partially (PR) received six more courses; patients whose disease progressed were excluded from the study. Among patients with measurable disease, the following clinical response rates were observed: PC = 20% CR, 34.3% PR, 14.3% stable disease, and 31.4% progression; PAC = 40.6% CR, 15.6% PR, 12.5% stable disease, and 31.3% progression. In the 75 patients submitted to second look, the results have been the following: PC = 39.5% CR, 36.8% PR, 7.9% stable disease, and 15.8% progression; PAC = 62.2% CR, 18.9% PR, 10.8% stable disease, and 8.1% progression. The difference in surgical complete response in favor of the PAC regimen is significant (P less than .05). Median survival and progression-free survival were 800 and 400 days, respectively, for PAC arm; median survival and progression-free survival were 680 and 380 days, respectively, for PC. These differences are not significant. Probability of survival was affected by FIGO stage, amount of residual disease, histology, performance status, and response at second look, while no influence was observed according to grade of tumor differentiation and age. Our results demonstrate the usefulness of doxorubicin in terms of surgical CR. 相似文献
15.
The plasma pharmacokinetics of adriamycin after intrapleural administration have been studied. The maximum plasma concentration found after intrapleural instillation of 50 mg was 100 ng ml-1, the adriamycin half-life being about 2.5 h. Large amounts of the drug are adsorbed from the pleura. Hence risks for cardiomyopathy, previously associated with the repeated intravenous administration of adriamycin, must also be considered after intrapleural administration. 相似文献
16.
P F Conte M Bruzzone F Carnino S Chiara M Donadio V Facchini P Fioretti G Foglia A Gadducci L Gallo 《Journal of clinical oncology》1991,9(4):658-663
One hundred sixty-four patients with stage III-IV epithelial ovarian carcinoma were randomized to receive cisplatin (CDDP) 50 mg/mq, doxorubicin 45 mg/mq, and cyclophosphamide 600 mg/mq (PAC) or carboplatin 200 mg/mq, doxorubicin 45 mg/m2, and cyclophosphamide 600 mg/mq (CAC). To administer equitoxic doses at each cycle, the drug dosages were adjusted according to the hematologic toxicities experienced after the previous course; 44.7% of CAC and 21.1% of PAC patients required a dosage reduction at the second course (P = .002). Neither CAC nor PAC caused any clinically relevant neuro-nephrotoxicity; however, CDDP was administered with hydration and forced diuresis, while carboplatin was administered by rapid intravenous (IV) infusion. After six cycles, response rates were superimposable: 62.5% and 66.6% for CAC and PAC, respectively; pathologic complete responses (pCRs) were 16.7% for CAC and 23.2% for PAC; among patients with more than 2 cm residual disease, PAC induced more pCRs than CAC (eight of 52 or 15.4% v one of 42 or 2.4%, P = .07). Median survivals and progression-free survivals (PFSs) were 22.6 and 13.2 months for PAC, and 23.1 and 15.5 months for CAC, respectively; these differences are not significant. In conclusion, this trial demonstrates that equitoxic doses of PAC or CAC result in a similar response rate, PFS, and survival. 相似文献
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Franco Pannuti Carlo M Camaggi Elena Strocchi Raffaella Comparsi 《Cancer chemotherapy and pharmacology》1987,19(4):311-314
Summary Medroxyprogesterone acetate (MAP) plasma pharmacokinetics was followed up in a total of 30 New Zealand rabbits after i. v. administration (0.1, 0.5, and 1.0 mg/kg) of either an aqueous suspension or a homogeneous solution of the drug in dimethylsulphoxide (DMSO). A well-defined triphasic decay of MAP plasma levels was noticeable in the animals treated with DMSO solutions. A delayed concentration peak was often present when aqueous suspensions were used, so if is not feasible to fit the experiment with simple polyexponential equations. Model-independent pharmacokinetic analysis (statistical moment theory) revealed a significant dependence of plasma clearance and mean residence time on the dose administered in both conditions.Supported in part by contract CNR, No. 85.02282.44 (Progetto finalizzato Oncologia) 相似文献
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Anttila Markku I. Sotaniemi Eero A. Kairaluoma Matti I. Mokka Risto E. Sundquist Hannu T. 《Cancer chemotherapy and pharmacology》1983,10(3):150-153
The pharmacokinetics of ftorafur (FT), an antineoplastic agent, has been studied in seven cancer patients by determining concentrations of the unchanged compound in serum after single IV and PO doses of 2 g FT. Serum drug concentrations were determined by a new quantitative thin-layer chromatographic method. After IV administration, the mean half-lives of the distribution phase and elimination phase were 1.0 h and 7.6 h, respectively. Total serum clearance was 69 ml/h . kg and the apparent volume of distribution was 0.66 l/kg. Following PO administration there was a short lag-time, 11 min, before the appearance of FT in peripheral serum, and the maximum concentration in peripheral serum was achieved in 3.2 h. Oral absorption was complete and no significant first-pass metabolism could be observed. FT elimination, measured in serum taken from the portal vein and a peripheral vein, occurred substantially at the same rate after IV and PO administration. In contrast, after the PO dose FT appeared in the portal serum significantly earlier than in the peripheral serum, resulting in a difference of 1.7 h in the time of maximum serum concentration. This indicates fast gastrointestinal absorption of FT but hepatic retention (without metabolism) before the appearance of FT in the peripheral serum. 相似文献