The <i>CMF</i>‐regimen. Modulation of cyclophosphamide uptake and clearance by methotrexate and fluorouracil

Bruijn, E. A. de; Geng, Yayuan; Hermans, J.; Driessen, O.

doi:10.1002/ijc.2910450526

Cited by 9 publications

(4 citation statements)

References 10 publications

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“…DeBruijn et al (1990) demonstrated in rats that when methotrexate and fluorouracil are given with oral cyclophosphamide its AVC is increased by 50% over that seen with the use of oral cyclophosphamide alone; this effect appears to be due to a reduction in cyclophosphamide clearance. No evidence of a pharmacokinetic drug interaction has been demonstrated in patients receiving cyclophosphamide; an alteration in the clearance may not alter the effect, unless exposure to metabolites is also influenced.…”

Section: Drug Interactionsmentioning

confidence: 90%

Clinical Pharmacokinetics of Cyclophosphamide

Moore

1991

Clinical Pharmacokinetics

255

131

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Cyclophosphamide has been in clinical use for the treatment of malignant disease for over 30 years. It remains one of the most useful anticancer agents, and is also widely used for its immunosuppressive properties. Cyclophosphamide is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard. Sensitive and specific methods are now available for the measurement of cyclophosphamide, its metabolites and its stereoisomers in plasma and urine. The pharmacokinetics of cyclophosphamide have been understood for many years; those of the cytotoxic metabolites have been described more recently. The pharmacokinetics are not significantly altered in the presence of hepatic or renal insufficiency. As activity resides exclusively in the metabolites, whose pharmacokinetics are not predicted by those of the parent compound, correlations between cyclophosphamide pharmacokinetics and pharmacodynamics have not been demonstrated. Cyclophosphamide is used in doses that range from 1.5 to 60 mg/kg/day. A steep dose-response curve exists, and reductions in dose can lead to unfavourable outcomes. Myelosuppression is the dose-limiting toxicity, although in the setting of bone marrow transplantation, escalation beyond that dosage range is limited by cardiac toxicity. Longer term complications of cyclophosphamide therapy include infertility and an increased incidence of second malignancies. Cellular sensitivity to cyclophosphamide is a function of cellular thiol concentration, metabolism by aldehyde dehydrogenases to form inactive metabolites, and the ability of DNA to repair alkylated nucleotides. Whether alteration of these cellular functions will lead to further improvements in clinical outcomes is an area of active investigation.

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Section: Drug Interactionsmentioning

confidence: 90%

Clinical Pharmacokinetics of Cyclophosphamide

Moore

1991

Clinical Pharmacokinetics

255

131

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“…De Bruijn et al [14,15] have shown an increase in the elimination half-life of 5-FU and the area under the plasma concentration time curve of CY in rats after the CMF regi men, which would point to the increased plas ma concentration of these cytostatic agents. Despite this possibility, 5-FU and CY admin istered in the CMF regimen did not seem to precipitate nephrotoxicity in rats.…”

Section: Discussionmentioning

confidence: 99%

“…De Bruijn et al [ 12] claim that toxicity estimated on the basis of deaths, myelosuppression, and gastrointestinal side effect in the CMF treat ment group was surprisingly low. Therapeutic benefits of combined chemotherapy have also been evaluated at the pharmacokinetic level in experiments on rats [13][14][15]. De Bruijn et al [13] showed that after CMF administra tion, MTX clearance increases; 5-FU may affect the distribution phase, and CY the elimination phase of MTX.…”

Section: Discussionmentioning

confidence: 99%

Effect of Some Anticancer Drugs and Combined Chemotherapy on Renal Toxicity

Skrętkowicz

Sekulska²,

Danilewicz³

et al. 1996

Neurosignals

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The nephrotoxic action of anticancer drugs such as nitrogranulogen (NG), methotrexate (MTX), 5-fluorouracil (5-FU) and cyclophosphamide (CY) administered alone or in combination [MTX+5-FU+CY (CMF)] was evaluated in experiments on Wistar rats. After drug administration, creatinine concentrations in the plasma and in the urine of the rats were determined, as well as creatinine clearance. Histopathologic evaluation of the kidneys was also performed. After MTX administration a significant increase (p = 0.0228) in the plasma creatinine concentration and a significant (p = 0.0001) decrease in creatinine clearance was noted compared to controls. After the administration of NG, 5-FU and CY neither a statistically significant increase in creatinine concentration nor an increase in creatinine clearance was observed compared to the group receiving no cytostatics. Following polytherapy according to the CMF regimen, a statistically significant decrease (p = 0.0343) in creatinine clearance was found, but creatinine concentration did not increase significantly compared to controls. CY caused hemorrhagic cystitis in 40% of rats, but it did not cause this complication when combined with 5-FU and MTX. Histologic changes were found in rat kidneys after administration of MTX, CY and NG, while no such change was observed after 5-FU and joint administration of MTX+5-FU+CY compared to controls. Our studies indicate that nephrotoxicity of MTX + 5-FU+CY administered jointly is lower than in monotherapy.

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“…A further extensive study of the CMF regimen has shown that both fluorouracil and methotrexate cause an increase in AVC and a decrease in the rate of absorption of orally administered cyclophosphamide in rats (De Bruijn et al 1990). The reasons for this are complex and the reader is referred to the original paper for further explanation.…”

Section: Cyclophosphamidementioning

confidence: 98%

Pharmacokinetic Drug Interactions with Anticancer Drugs

Loadman

Bibby

1994

Clinical Pharmacokinetics

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Drug dosage is of paramount importance in the treatment of cancer, the aim being to optimise drug exposure with a view to maximising antitumour effect and minimising normal tissue toxicity. Pharmacokinetic parameters of anticancer drugs vary considerably from patient to patient. Most clinically useful drug regimens consist of a cocktail of drugs with different mechanisms of action and hence different toxicity profiles. Therefore, it is even more difficult to optimise drug dosage for individual patients. Variability in the pharmacokinetic profile of anticancer agents in individual patients can be further complicated by pharmacokinetically based drug interactions between different anticancer drugs or anticancer drugs and other concomitant medication. Most of the reported studies provide useful information and identify major interactions, but many also demonstrate the difficulty in identifying therapeutically important drug interactions in patients. Even with all the problems associated with acquiring suitable data from cancer patients it is clear that drug interactions do occur and that these can be clinically significant. It is important that potential interactions are identified early in the drug development of new anticancer drugs. This may be made possible by the rapid improvements in analytical techniques and the availability of more appropriate clinically relevant model systems. Therefore, the therapeutic significance of any detected interactions may be assessed, and steps to avoid them may be established, before the drug is under clinical investigation.

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The CMF‐regimen. Modulation of cyclophosphamide uptake and clearance by methotrexate and fluorouracil

Cited by 9 publications

References 10 publications

Clinical Pharmacokinetics of Cyclophosphamide

Clinical Pharmacokinetics of Cyclophosphamide

Effect of Some Anticancer Drugs and Combined Chemotherapy on Renal Toxicity

Pharmacokinetic Drug Interactions with Anticancer Drugs

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