The metabolism of cyclophosphamide. Dose dependency and the effect of long-term treatment with cyclophosphamide

Mouridsen, H. T.; Faber, O.; Skovsted, L.

doi:10.1002/1097-0142(197602)37:2<665::aid-cncr2820370209>3.0.co;2-d

Cited by 43 publications

(14 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, increased activity of dihydrouracil dehydrogenase in the liver was measured, suggesting that increased degradation of 5-fluorouracil could be induced by chronic treatment with the drug. Changes in drug metabolism have been reported after repeated administration of daunomycin in rats (Nooter et al, 1984). Decreased intestinal absorption of methotrexate was also suggested in the rat following repeated oral administration of the drug (Sonnevald et al, 1985).…”

supporting

confidence: 92%

“…One possible mechanism is that multiple doses of cyclo have an inducing effect on enzymes involved in the metabolism of cyclo, although in another clinical study, no change in cyclo metabolism was found in patients after 22 days of treatment with daily doses of 2mgkg-1 (Mouridsen et al, 1976). Our bioassay failed to detect significant differences of cytotoxic cyclo metabolite levels in the blood between animals in the cyclo-cyclo group and the NaCl-cyclo group.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Tumour response to chemotherapy in animals that have been treated with the same drugs prior to tumour implantation: A model for studying host effects on apparent drug resistance

Luk

Tannock²

1988

Br J Cancer

View full text Add to dashboard Cite

Summary The outcome of cancer chemotherapy is determined by an interplay of multiple factors between the host, the tumour, and the drugs administered. Most studies have emphasised the development or selection of drug resistant tumour cells. However, repeated drug treatment of the host may lead to changes (e.g. in pharmacokinetics, host defences, etc.) which can influence the subsequent response of the tumour. In this study, we present a model to investigate the role of the host in the development of drug resistance. A drug is administered repeatedly to animals prior to tumour implantation, and tumour response is then evaluated following treatment with the same drug in pretreated and control animals.To illustrate the method, cyclophosphamide was administered weekly for 4 weeks to C3H mice before implantation of the KHT tumour. Tumour growth delay was then compared after one further treatment of cyclophosphamide in this group of animals to that in control mice which had not received the cyclophosphamide pretreatment. Our results indicate that cyclophosphamide produces only a small effect on the host in this system, but the model is a potentially useful one to investigate the contribution of the host in the acquisition of drug resistance.

show abstract

supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Tumour response to chemotherapy in animals that have been treated with the same drugs prior to tumour implantation: A model for studying host effects on apparent drug resistance

Luk

Tannock²

1988

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…We now show that neither tumor growth inhibition nor antivascular activities of LDM CPA are compromised when mice are pretreated with LDM CPA for The observed strain differences in the absolute 4-OH-CPA levels and various pharmacokinetic parameters are not completely unexpected given preclinical and clinical evidence of (epi)genetic heterogeneity of the enzymes involved in CPA metabolism (20,33). Although differences exist between human and murine CPA biotransformation (35), our results are in accordance with a study by Mouridsen et al (36). Using radioactively labeled CPA, the authors did not observe a change in the pharmacokinetic properties of CPA in patients presenting with advanced malignancies given 2 mg/kg/d of CPA for a period of 13 to 33 days.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Emmenegger

Shaked

Man

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Prolonged, frequently administered low-dose metronomic chemotherapy (LDM) is being explored (pre)clinically as a promising antiangiogenic antitumor strategy. Although appealing because of a favorable side effect profile and mostly oral dosing, LDM involves new challenges different from conventional maximum tolerated dose chemotherapy. These include possible altered pharmacokinetic characteristics due to long-term drug exposure potentially resulting in acquired resistance and increased risk of unfavorable drug interactions. We therefore compared the antitumor and antivascular effects of LDM cyclophosphamide (CPA) given to mice that had been pretreated with either LDM CPA or normal saline, obtained blood 4-hydroxy-CPA (activated CPA) concentrations using either gas chromatography/mass spectrometry or liquid chromatography/tandem mass spectrometry in mice treated with LDM CPA, and measured hepatic and intratumoral activity of enzymes involved in the biotransformation of CPA and many other drugs [i.e., cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase]. Exposure of mice to LDM CPA for z8 weeks did not compromise subsequent activity of LDM CPA therapy, and biologically active 4-hydroxy-CPA levels were maintained during long-term LDM CPA administration. Whereas the effects on CYP3A4 were complex, aldehyde dehydrogenase activity was not affected. In summary, our findings suggest that acquired resistance to LDM CPA is unlikely accounted for by altered CPA biotransformation. In the absence of reliable pharmacodynamic surrogate markers, pharmacokinetic parameters might become helpful to individualize/optimize LDM CPA therapy. LDM CPA-associated changes of CYP3A4 activity point to a potential risk of unfavorable drug interactions when compounds that are metabolized by CYP3A4 are coadministered with LDM CPA. [Mol Cancer Ther 2007;6(8):2280 -9]

show abstract

“…Similarly, cyclophosphamide (a congener of ifosfamide) does not show dose-dependent pharmacokinetics at doses used in clinical practice (Mouridsen et al, 1976;Wilkinson et al, 1983). The most likely explanation for the contradictory data of Allen et al (1976) is that the radiolabelled ifosfamide they used was randomly labelled with 14C on the carbon atoms of either of the chloroethyl side chains.…”

Section: Discussionmentioning

confidence: 99%

The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.

Lewis

Fitzgerald

Mohan

et al. 1991

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 We investigated the pharmacokinetics of ifosfamide 5 g m-2 given by two regimens.Six patients (one female), median age 55 (range 40-71) years, all with lung cancer received 5 g m-2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23-72) years were studied on seven treatment occasions with 5 g m-2 ifosfamide (median ifosfamide dose 8.88 g) as a 24 h intravenous infusion with mesna. Plasma was assayed for ifosfamide by gas liquid chromatography and for alkylating activity by the nitrobenzylpyridine method. 2 After ifosfamide 5 g m-2 infused over 0.5 h, the decay of the plasma ifosfamide concentration was monoexponential with a median (range) t/2,z of 5.4 h (3.6-10.4 h).The median clearance was 60 ml min-1 (47-104) and the median volume of distribution was 388 (329-783) ml kg-'. Plasma nitrobenzylpyridine alkylating activity showed a biexponential decay in four patients and a monoexponential decay in two, with a median AUC of 102 (24-177) nmol nor nitrogen mustard eq h ml-'.3 When ifosfamide 5 g m-2 was given as a 24 h infusion, the decay of the plasma ifosfamide concentration was monoexponential, the median (range) t/2,z was 4.5 (3.4-6.1), the median volume of distribution was 563 (292-818) ml kg-1 and the median clearance was 79 (59-116) ml min-1. Plasma nitrobenzylpyridine alkylating activity decayed monoexponentially and the median AUC was 49 (45-131) nmol nor nitrogen mustard eq ml-' h.4 There was no evidence of saturation kinetics after high doses of ifosfamide. The clearance of ifosfamide at 5 g m-2 was similar whether it was given by short or 24 h intravenous infusion and was comparable with that observed after low doses of ifosfamide.

show abstract

The metabolism of cyclophosphamide. Dose dependency and the effect of long-term treatment with cyclophosphamide

Cited by 43 publications

References 9 publications

Tumour response to chemotherapy in animals that have been treated with the same drugs prior to tumour implantation: A model for studying host effects on apparent drug resistance

Tumour response to chemotherapy in animals that have been treated with the same drugs prior to tumour implantation: A model for studying host effects on apparent drug resistance

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.

Contact Info

Product

Resources

About