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1.
Jacques Robert Alain Monnier Nathalie Poutignat Patrice Hérait 《Cancer chemotherapy and pharmacology》1991,29(1):75-79
Summary We evaluated the pharmacokinetics of pirarubicin during 16 courses of therapy in 4 patients suffering from breast cancer who were treated with an association of pirarubicin (30–60 mg/m2 according to the hematologic tolerance to the previous course, the first course being given at a dose of 40 mg/m2) and continuous infusions of 5-fluorouracil (750 mg/m2 daily for 5 days). Pirarubicin's pharmacokinetics and metabolism were linear within this dose range; the metabolites identified were pirarubicinol, doxorubicin and doxorubicinol (AUC ratios of metabolite/pirarubicin were 0.6, 0.64 and 0.57 respectively). Pirarubicin's decay from plasma followed a twocompartmental pattern, showing half-lives of 15.6 min and 16.6 h: the total plasma clearance of the drug was 140 l/h–1/m–2, and the total volume of distribution was 2,830 l/m2. A relationship was observed between some pharmacokinetic parameters and the toxic effects of the drug: the percentage of survival of granulocytes was significantly correlated with the AUC values for doxorubicin and doxorubicinol, whereas that of platelets was significantly correlated with the AUC values for pirarubicin and pirarubicinol. This is the first study to demonstrate a pharmacokinetic/pharmacodynamic relationship for pirarubicin. 相似文献
2.
The compatibility and stability at room temperature for up to 7 days of a three-drug admixture of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) was established permitting the practical delivery of the combination as an infusion in an ambulatory setting. Fourteen patients received 20 courses of CMF administered on a continuous infusion schedule for 14 days of a 28-day cycle. The dose rates were fixed for 5-FU (300 mg/M2/day) and methotrexate (0.75 mg/M2/day). The cyclophosphamide dose was escalated from 25 to 50, 75, and 100 mg/M2/d. Leukopenia and thrombocytopenia were observed in two of five patients receiving the maximal dose of cyclophosphamide. No other toxicities were observed including alopecia, stomatitis or liver function abnormalities. This Phase I trial suggests that the cumulative doses of cyclophosphamide, methotrexate, and 5-FU are comparable to the maximum doses delivered as single agent infusions. Furthermore, when the infusion CMF is compared to the "standard" bolus schedule for CMF, the infusion schedule delivers 116%, 8%, and 350% of the respective three component drugs (cyclophosphamide, methotrexate, and 5-FU). 相似文献
3.
L. J. van Warmerdam S. Rodenhuis E. van der Wall R. A. Maes J. H. Beijnen 《British journal of cancer》1996,73(8):979-984
The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR. 相似文献
4.
Chinnaswamy G Errington J Foot A Boddy AV Veal GJ Cole M 《European journal of cancer (Oxford, England : 1990)》2011,47(10):1556-1563
Introduction
In order to better understand the impact of high-dose on the pharmacokinetics and metabolism of cyclophosphamide, a pharmacological study was performed in children with malignant mesenchymal tumours with metastatic disease.Methods
Patients received four courses of chemotherapy including two courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and the metabolites 4-ketocyclophosphamide, dechloroethylcyclophosphamide and carboxyphosphamide were determined on days 1, 2 and 3 of each course. A population pharmacokinetic model for cyclophosphamide was developed using non-linear mixed effects modelling and metabolite AUC values were compared between days and courses.Results
Data were available on 21 cyclophosphamide courses from 15 patients. A one compartment model, incorporating a term in surface area for both CL and V, best described cyclophosphamide pharmacokinetics. Typical CL and V on day 1 of treatment for a patient with a SA of 1.4 m2 were 4.3 L/h and 28.5 L, respectively. On days 2 and 3 CL increased by 88% (95% CI, 72-105%) and 125% (95% CI, 108-145%) over day 1 levels; V increased by 14% (95% CI, 5-23%) on days 2 and 3. V tended to be larger for males than similarly sized females but no effect of age was found upon CL or V. Significant increases in metabolite AUCs were observed on days 2 and 3 compared to day 1 and a significant increase in CXCP AUC from course 1 to course 3.Conclusion
Administration of high-dose cyclophosphamide over several days results in an increase in metabolism, possibly by induction of the activation pathway. This induction is effectively reversed following a four week period between cyclophosphamide doses. The degree of intersubject variation in cyclophosphamide elimination is largely accounted for by body surface area and is less than previously reported. 相似文献5.
M Gusella G Crepaldi C Barile A Bononi D Menon S Toso D Scapoli L Stievano E Ferrazzi F Grigoletto M Ferrari R Padrini 《Annals of oncology》2006,17(11):1656-1660
BACKGROUND: The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied. PATIENTS AND METHODS: One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle. RESULTS: The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients. CONCLUSIONS: A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance. 相似文献
6.
Batey MA Wright JG Azzabi A Newell DR Lind MJ Calvert AH Boddy AV 《European journal of cancer (Oxford, England : 1990)》2002,38(8):1081-1089
Despite the success of adjuvant cyclophosphamide, methotrexate (MTX), 5-fluouracil (5-FU) (CMF) treatment for early stage breast cancer, more than 35% of patients die within 5 years of diagnosis. Optimisation of the dose of each component drug may improve survival and reduce toxicity. In this study, the pharmacokinetics of intravenous (i.v.) cyclophosphamide (600 mg/m(2)), MTX (40 mg/m(2)) and 5-FU (600 mg/m(2)) were determined in 46 women, with data on two consecutive courses available for 41 patients. A population analysis using NONMEM was performed to investigate the effect of patient covariates on pharmacokinetics (PK), and to estimate the relative magnitude of interindividual and interoccasion variability. Patient weight had a significant influence on the clearance of cyclophosphamide and on the volume of central compartment for MTX, whose clearance was dependent on renal function. For all three drugs, interoccasion variability was of the same order (20-40%) as that between individuals, suggesting a limited potential for dose-optimisation of this regimen. 相似文献
7.
Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T(0) to T(72) hours (AUC(0--72)) and methotrexate AUCs were evaluated using MW/PHARM 3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 micromol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C 677 T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well. 相似文献
8.
Cesare Guglielmi Sergio Amadori Anna P. Anselmo Carlo D. Baroni Carissimo Biagini Giuseppe Cimino Giuseppe Papa Franco Mandelli 《Cancer investigation》1987,5(3):159-169
An intensive treatment program was developed to achieve durable remissions in a high proportion of previously untreated patients with advanced stages of diffuse high-grade non-Hodgkin's lymphoma (NHL). Fifty-six patients (15-68 years) received a course of F-MACHOP (5-fluorouracil, methotrexate, cytosine-arabinoside, cyclophosphamide, doxorubicin, vincristine, and prednisone) every 3-4 weeks for 6 courses. Cycle active drugs were sequentially administered to expose rapidly proliferating tumor cells to the synergistic effects of these agents throughout the cell cycle. Forty-three patients achieved complete remission (77%) and 80% of the complete responders are projected to be alive and disease-free at 4'A years (median follow-up 33 months). Up to 70% of all patients are predicted to be alive at 5 years. Bulky tumor, “B”-symptoms and lymphoblastic histology were poor prognostic factors, particularly when associated with clinically detectable disease after three courses. Toxicity included transitory myelodepression in most patients (2 septic deaths). This protocol provides effective and tolerable therapy for the majority of patients with advanced stages of diffuse aggressive NHL. 相似文献
9.
There are no established guidelines for detoxification for most cases of overdosage or intoxication with cytostatic drugs. Little is known about the dialysability of cytostatic drugs. To obtain further information on the dialysability of cytostatic drugs, human plasma was incubated with cytostatic drugs and dialysed in vitro using "mini-modules" with capillaries identical to clinical use. Cytotoxicity before and after dialysis was measured in a biological test system using permanent human lymphoblast cultures (LS2). The 20 cytostatic drugs studied could be categorised as follows: Good dialysability in vitro: methotrexate, 5-fluorouracil, cytarabine, actinomycin D, mitomycin C, 4-OH-cyclophosphamide, ifosfamide, melphalan, dacarbazine, cisplatin. Intermediate dialysability in vitro: adriamycin, epirubicin, carmustine. Ineffective dialysability in vitro: daunorubicin, vincristine, vinblastine, vindesine, etoposide, teniposide, mitoxantrone. These in vitro results cannot be transferred automatically into the in vivo situation because of specific drug distribution and metabolic rates. Considering pharmacokinetic data, the following recommendations can be made for practical clinical purposes: Detoxification by hemodialysis in vivo: Possibly effective: Methotrexate, 5-fluorouracil, mytomicin C, cyclophosphamide, ifosfamide, melphalan, carmustine, dacarbazine. Ineffective: Adriamycin, epirubicin, daunorubicin, mitoxantrone, actinomycin D, etoposide, teniposide, vincristine, vinblastine, vindesine, cytarabine, cisplatin. 相似文献
10.
M Yamauchi A Ito Y Kodera K Kondo H Nakahara S Nagai T Kuzuya T Satta K Ito H Takagi 《Gan to kagaku ryoho. Cancer & chemotherapy》1992,19(4):463-468
Gastric cancer sometimes spread to peritoneal surfaces in the absence of lymphatic or hematogenous metastases. For the treatment of peritoneal carcinomatosis, we applied large volume intraperitoneal chemotherapy (L.V.I.C.). In L.V.I.C., drugs were administered with large volume of saline through the reservoir buried in the subcutaneous tissue of the abdominal wall. We used mitomycin C (MMC), 5-fluorouracil (5-FU) and CDDP and examined the pharmacokinetics of these drugs when they were administered by this method to the patients of peritoneal carcinomatosis. A marked pharmacokinetic advantage was observed when 5-FU and CDDP were administered. AUC of these drugs were much larger than that of MMC. In vitro sensitivity test (SDI test) was useful for the selection of adequate drugs for each patient. On this method, drugs were distributed widely in the abdominal cavity and the patients could be taken this treatment repeatedly as out-patient. L.V.I.C. seems to fulfill the need for a safe, effective and acceptable delivery system of intraperitoneal chemotherapy. 相似文献
11.
BACKGROUND: Irinotecan (CPT-11) in combination with 5-fluorouracil/folinic acid is used successfully for first-line treatment of metastatic colorectal cancer. Capecitabine (CCB) represents a very convenient alternative to 5-fluorouracil, either as single agent or in a combination of regimens acting synergistically and with the potential to further improve efficacy. Both CPT-11 and CCB need to be activated by human carboxyl esterases, therefore a probable pharmacokinetic drug interaction was checked. PATIENTS AND METHODS: Ten patients suffering from advanced colorectal cancer were enrolled in this trial. CPT-11 was administered as a 30-min i.v.-infusion (70 mg/m2) weekly. CCB was given p.o. twice daily for two weeks (2,000 mg/m2 daily) starting the day after the first CPT-11 infusion. Plasma samples were analysed during/after the first (MONO) and third (CAPIRI) CPT-11 infusion. RESULTS: CCB did not alter CPT-11 plasma disposition, and no significant changes in c(max), AUC(last), Vdss and Cl(tot) during CAPIRI treatment could be observed. However, co-administration of CCB appeared to decrease SN-38 (the cytotoxic CPT-11 metabolite) plasma concentrations during the first three hours after initiation of CPT-11 infusion, with strongly time-dependent plasma percentage differences between control and CAPIRI treatment (p < 0.005, R = 0.981). Co-administration of CCB also had a similar impact on the initial plasma disposition of SN-38gluc, but not on that of the APC metabolite. CONCLUSION: Overall, our findings indicate that, while the administration of CCB resulted in reversible lower formation rates of SN-38 and SN-38gluc, it did not have a significant impact on CPT-11 pharmacokinetics. 相似文献
12.
Codacci-Pisanelli G Pinedo HM Lankelma J Van Groeningen CJ Van Kuilenburg AB Van Gennip AH Peters GJ 《Journal of chemotherapy (Florence, Italy)》2005,17(3):315-320
The pharmacokinetics of 5-fluorouracil (5FU) have been related to toxicity and antitumor activity, in particular for continuous infusion schedules, but to a lesser extent for frequently used bolus injections. The use of intensive sampling schedules limits the application of pharmacokinetics to optimize individual dosing or to define the ideal combination with other drugs. We therefore reanalyzed a pharmacokinetic study in order to develop a limited sampling schedule. Patients received escalating doses of 5FU at 500, 600 and 720 mg/m2 as a bolus until toxicity developed. Blood samples were analyzed until 24 h after administration. The area under the concentration time curve from 0-90 min (AUC(0-90)) was strongly correlated with dose and also with toxicity (p = 0.0009). The 5FU concentrations at 30 and 60 min were correlated to the AUC(30-240) and to that of the AUC(0-90) (r2 = 0.970). The use of limited sampling (30, 60, 90 min) in a patient given 353 mg/m2 5FU with severe toxicity at initial dosing at 500 mg/m2 revealed that the AUC(0-90) at 353 mg/m2 was higher than the normal AUC(0-90) for 500 mg/m2. This patient appeared to have an 8-fold lower activity of the 5FU degradation enzyme dihydropyrimidine dehydrogenase. Limited sampling will allow us to define potential aberrant kinetics of pharmacokinetic interaction of 5FU with other drugs being developed for treatment of colorectal cancer. 相似文献
13.
David H Salinger Jeannine S McCune Aaron G Ren Danny D Shen John T Slattery Brian Phillips George B McDonald Paolo Vicini 《Clinical cancer research》2006,12(16):4888-4898
PURPOSE: Dose-related toxicity of cyclophosphamide may be reduced and therapeutic efficacy may be improved by pharmacokinetic sampling and dose adjustment to achieve a target area under the curve (AUC) for two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM). To facilitate real-time dose adjustment, we developed open-source code within the statistical software R that incorporates individual data into a population pharmacokinetic model. EXPERIMENTAL DESIGN: Dosage prediction performance was compared to that obtained with nonlinear mixed-effects modeling using NONMEM in 20 cancer patients receiving cyclophosphamide. Bayesian estimation of individual pharmacokinetic parameters was accomplished from limited (i.e., five samples over 0-16 hours) sampling of plasma HCY and CEPM after the initial cyclophosphamide dose. Conditional on individual pharmacokinetics, simulations of the AUC of both HCY and CEPM were provided for a range of second doses (i.e., 0-100 mg/kg cyclophosphamide). RESULTS: The results compared favorably with NONMEM and returned accurate predictions for AUCs of HCY and CEPM with comparable mean absolute prediction error and root mean square prediction error. With our method, the mean absolute prediction error and root mean square prediction error of AUC CEPM were 11.0% and 12.8% and AUC HCY were 31.7% and 44.8%, respectively. CONCLUSIONS: We developed dose adjustment software that potentially can be used to adjust cyclophosphamide dosing in a clinical setting, thus expanding the opportunity for pharmacokinetic individualization of cyclophosphamide. The software is simple to use (requiring no programming experience), reads individual patient data directly from an Excel spreadsheet, and runs in less than 5 minutes on a desktop PC. 相似文献
14.
Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil 总被引:1,自引:0,他引:1
Recent reports have documented an increase of thrombotic complications in patients with carcinoma of the breast receiving chemotherapy regimens containing cyclophosphamide, methotrexate, and 5-fluorouracil. The authors studied blood from nine such patients screening for abnormalities that might predispose to thrombosis or indicate that the coagulation cascade had been activated. Six of the patients were in the adjuvant setting, and three had metastatic disease. Samples were collected from each patient before, during, and after completion of the chemotherapy in question. In each patient a statistically significant decline in functional protein C activity (P = 0.001) was demonstrated at midtherapy. In seven of nine patients functional protein C level normalized after the cessation of therapy. No other positive results were found. The authors conclude that the combination of cyclophosphamide, methotrexate, and 5-fluorouracil, when administered to patients with a diagnosis of carcinoma of the breast, causes a reversible decline in the activity of protein C. 相似文献
15.
G R Glae L M Atkins S J Meischen A B Smith E M Walker 《Journal of the National Cancer Institute》1976,57(6):1363-1366
Six antitumor platinum compounds were used in combination with cyclophosphamide plut 1 of 7 other antitumor drugs for treatment of L1210 leukemia in B6D2F [C57BL/6 X DMA/2) F] mice. Data obtained from each three-agent regimen were compared with those obtained after administration of each compound alone and each appropriate two-agent combination. No cure (greater than 60-day survival) was obtained with any compound used alone. Combination of cyclophosphamide with a platinum compound (Pt+CY) yielded a collective cure rate of 193/420, and the addition of a third cure rate to 290/420 (P less than 0.001). Certain regimens produced 100% cure rates. The most effective drugs when used in combination with PT+CY were cytosine arabinoside, 5-fluorouracil, hydroxyurea, and Yoshi-864. Adriamycin, methotrexate, and vincristine were less effective at the doses used. Toxicity, as evidenced by maximum weight loss, was slightly greater with the three-agent combinations than with the Pt+CY regimens. 相似文献
16.
This review describes how genetic differences among patients may change the therapeutic outcome in cancer chemotherapy. Severe toxicity in genetically predisposed patients is predominantly associated with mutations in drug metabolism enzyme genes, and an update on genetic intolerance to 6-mercaptopurine, 5-fluorouracil, and irinotecan is provided. Moreover, recent findings pointed out that the methylenetetrahydrofolate reductase (MTHFR) C677T mutation might change patient susceptibility to the toxic effects of the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen and raltitrexed. Finally, it is emerging that not only toxicity, but also response to chemotherapy could be influenced by pharmacogenetic determinants, and the clinical relevance of polymorphisms in thymidylate synthase (TS) and glutathione-S-transferase (GST) genes is discussed. 相似文献
17.
The general basis of pharmacokinetics are summarized with the clinical aims of a better utilisation of drugs by the application pharmacokinetic data. The subject is illustrated by some antineoplastic agents especially on high dose methotrexate regimens and clinical use of 5 FU. A pharmacokinetic model may be described with the first agent but for 5 FU no specific model has yet been demonstrated. Some examples of studies on adriamycin and cytosine arabinoside are then given. 相似文献
18.
Urien S Fumoleau P Campone M Kerbrat P Bonneterre J Fargeot P Deporte-Fety R 《Cancer chemotherapy and pharmacology》2003,52(2):99-107
PURPOSE: The pharmacokinetics of ftorafur, 5-fluorouracil (5FU) and uracil were investigated in order to built a population pharmacokinetic model for the anticancer drug UFT, administered with leucovorin and vinorelbine. METHODS: A total of 31 patients with metastatic breast cancer were treated with escalating oral doses of UFT (300 to 500 mg per day) plus leucovorin (90 mg per day) in combination with intravenous vinorelbine (15 to 25 mg/m(2)). Concentration-time data were obtained on days 1, 8, 15 and 21 of cycle 1. RESULTS: Of the 31 patients treated, 30 were available for the pharmacokinetic analysis. Ftorafur, 5FU and uracil appeared rapidly in plasma and showed large interpatient variations. Ftorafur concentrations were higher than those of 5FU and uracil. AUC significantly increased between day 1, and days 8, 15 and 21. Ftorafur C(max) and AUC values were proportional to UFT dose, whereas C(max) and AUC values of 5FU and uracil were not linearly related to UFT dose. The pharmacokinetics of ftorafur were ascribed to a two-compartment open model in which 5FU was produced from the central compartment. The absorption and exponential distribution rate constants were assumed equal. The effect of uracil on 5FU elimination was straightforward, since no reasonable curve-fitting could be obtained for 5FU data when this covariate was not taken into account. The uracil concentration inducing a 50% reduction in 5FU elimination was 2.67 micro mol.l(-1). This result confirms the important role played by uracil as a competitive inhibitor of 5FU catabolism. CONCLUSION: A pharmacokinetic model for ftorafur and 5FU was developed and should be useful to further study drug interactions and establish dosing guidelines. 相似文献
19.
Misonidazole (MISO) has been shown to affect the pharmacokinetics of both cyclophosphamide (CY) and melphalan (MEL) in WHT mice resulting in increased plasma levels of the cytotoxic drugs. The effect is not solely due to the reduction in body temperature observed with large single doses of MISO, as a change in MEL pharmacokinetics was still observed when the mice were maintained at 37 degrees C. Inhibition of cytotoxic drug metabolism may also be a possible mechanism. Such a pharmacokinetic effect could account for part of the potentiation of MEL and CY action observed in tumours with large single doses of MISO. However, a chronic low dosing schedule of MISO did not affect the plasma half-life of either cytotoxic drug, although a significant potentiation of each drug in combination with a chronic MISO dose has been obtained in some tumours. These results suggest that potentiation of chemotherapeutic drug action by MISO in the clinical situation is unlikely to be due to changes in drug pharmacokinetics. 相似文献
20.
D S Alberts N Mason-Liddil P M Plezia D J Roe R T Dorr R F Struck J G Phillips 《Journal of the National Cancer Institute》1991,83(23):1739-1742
We previously reported that cimetidine but not ranitidine significantly enhances cyclophosphamide-induced bone marrow toxic effects and the appearance of cyclophosphamide alkylating species in a murine leukemia mouse model, and we advised caution in the use of cimetidine with microsomally metabolized anticancer drugs. Both drugs have been used for the treatment of gastric complications of chemotherapy. Using a randomized, double-blind, crossover study design, we have now evaluated the potential interaction of ranitidine with cyclophosphamide in seven cancer patients, who received two courses of cyclophosphamide, one with ranitidine and one with placebo. Four patients received ranitidine in the first course, and three received placebo. Ranitidine or placebo was started 3 days before a single dose of cyclophosphamide and given for 17 consecutive days. Ranitidine or placebo was given orally (300 mg/d), and cyclophosphamide (600 mg/m2) was given intravenously with [3H]cyclophosphamide (1000 muCi). Cyclophosphamide treatment was repeated at 4 weeks plus or minus 4 days. Blood samples were collected at intervals from 5 minutes to 24 hours after cyclophosphamide treatment and analyzed by thin-layer chromatography and radioassay for the drug and its metabolites. On days 0, 7, 14, and 21 after cyclophosphamide administration, complete blood cell counts, white blood cell differential counts, platelet counts, and SMA-17 were determined. The differences in mean nadir white blood cell counts, granulocyte counts, hemoglobin levels, and hematocrit values during ranitidine versus placebo treatment were not statistically significant. In a statistical but not a clinical sense, mean nadir platelet counts were significantly lower with ranitidine. There was a statistically significant increase in area under the curve for drug concentration in plasma x time (AUC) with ranitidine as well as a statistically significant decrease in the total-body clearance rate of the cyclophosphamide molecule. However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophosphamide and phosphoramide mustard was not statistically significant. The lack of toxicologic or metabolic interaction between ranitidine and cyclophosphamide suggests that ranitidine can be used safely with cyclophosphamide. 相似文献