Decreased half life of cyclophosphamide in patients under continual treatment

D’Incalci, Maurizio; Bolis, Giorgio; Facchinetti, T.; Mangioni, Costantino; Morasca, L.; Morazzoni, Paolo; Salmona, Mario

doi:10.1016/0014-2964(79)90198-1

Cited by 66 publications

(21 citation statements)

References 9 publications

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“…25 Area-under-curve (AUC) of concentration Â time pharmacokinetic studies have established that treatment with a high dose of alkylating agent administered over a short period of time, as in the case of bolus CPA treatment, yields the same overall amount of active metabolite, and hence equivalent cytotoxic activity, as when the alkylating agent is administered at a correspondingly lower concentration for a longer period of time. 26 In the present in vitro studies, a decrease in cellular capacity for CPA 4-hydroxylation was seen after 72 hours of continuous low-dose CPA treatment, but was not seen when the cells were exposed to bolus high-dose CPA (Fig 4). This difference may, in part, reflect the higher overall drug exposure of the continuous low-dose CPA-treated cells during the initial 3 day period (Fig 4e), as well as the drug-free recovery period available to the bolus high-dose CPA-treated cells but not the continuous low-dose CPAtreated cells.…”

Section: Discussionsupporting

confidence: 44%

Sustained P450 expression and prodrug activation in bolus cyclophosphamide-treated cultured tumor cells. Impact of prodrug schedule on P450 gene-directed enzyme prodrug therapy

2003

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Cytochrome P450-based gene therapy can substantially increase the sensitivity of tumor cells to P450-activated cancer chemotherapeutic prodrugs such as cyclophosphamide (CPA) without increasing host toxicity. While the role of 4-OH-CPA, the primary active metabolite of CPA, in eliciting tumor cell death is well established, the effect of 4-OH-CPA exposure on the capacity of P450-expressing tumor cells for continued metabolism and activation of CPA has not been investigated. The present study addresses this question and characterizes the impact of CPA dose and treatment schedule on the ability of P450-expressing tumor cells to sustain prodrug activation over time. 9L gliosarcoma cells expressing human P450 2B6 and treated with CPA in a continuous manner exhibited a time-and CPA dose-dependent decrease in P450-catalyzed CPA 4-hydroxylase activity. This decrease reflects a selective, 4-OH-CPA-induced loss of cellular P450 protein content. By contrast, when the P450-expressing tumor cells were treated with CPA as a single 8 hours exposure, cellular CPA 4-hydroxylase activity and P450 protein expression were substantially prolonged when compared to continuous prodrug treatment. This schedule-dependent effect of CPA was influenced by the level of P450 protein expressed in the tumor cells. At high P450 protein and activity levels, which could be achieved by culturing the tumor cells at high cell density, net production and release of 4-OH-CPA into the culture media was increased substantially. This increase fully offset the decline in CPA 4-hydroxylase activity as the tumor cells underwent CPAinduced apoptotic death. These findings demonstrate the impact of CPA dose and treatment schedule on the efficacy of P450 genedirected enzyme prodrug therapy, with bolus CPA treatment being compatible with sustained expression of P450 protein and maintenance of P450-dependent prodrug activation by the target tumor tissue.

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Section: Discussionsupporting

confidence: 44%

Sustained P450 expression and prodrug activation in bolus cyclophosphamide-treated cultured tumor cells. Impact of prodrug schedule on P450 gene-directed enzyme prodrug therapy

2003

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“…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. Otherwise, D'Incalci et al (37) described increased CPA clearance after oral administration of 100 mg/d of CPA for 6 to 13 months to cancer patients using GC. Unfortunately, the authors did not provide parameters such as the area under the curve of CPA at the beginning and after long-term CPA administration.…”

Section: Discussionmentioning

confidence: 99%

“…LC conditions were as follows: mobile phase A: 95% aqueous 2 mmol/L formic acid, pH 3.5 adjusted by ammonium hydroxide, 5% acetonitrile; mobile phase B: 100% acetonitrile; flow rate: 0.5 mL/min; gradient, 0 to 1 min, 70% A; 1 to 3.5 min, 70% to 30% A; 3.5 to 4.5 min, 30% to 70% A, 6-min equilibration at 70% A; and column: Phenomenex C 18 , 150 Â 3 mm, 3 Am, at 45jC. MS/MS conditions were as follows: Applied Biosystems 3200 Q-Trap instrument, in multiple reaction monitoring mode, m/z 472/221 (PBOX-H + - 35 Cl, 35 Cl), m/z 480/229 (PBOX-d 4 -H + - 37 Cl, 37 Cl); curtain gas 40 p.s.i. ; ion spray voltage, 5,500 V; temperature, 300jC; ion source gas 1, 40 p.s.i.…”

Section: Matrigel Plug Perfusion Assay and Circulating Endothelial Prmentioning

confidence: 99%

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

Emmenegger

Shaked

Man

et al. 2007

Molecular Cancer Therapeutics

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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]

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“…The latter finding suggests enzyme induction by cyclophosphamide and prednisone (Faber et al, 1974;D'Incalci et al, 1979 …”

Section: Discussionmentioning

confidence: 99%

Disposition of antipyrine in African patients with Hodgkin's lymphoma.

Juma

1987

Brit J Clinical Pharma

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KenyaThe pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half-life of antipyrine was 12.2 ± 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 ± 0.1 1 kg-' (mean ± s.d.) and the total body clearance was 40.7 ± 3.2 ml kg-1 h-1 (mean ± s.d.) in the healthy volunteers. The antipyrine half-life in the patients with advanced Hodgkin's lymphoma was 17.1 ± 2.7 h (mean ± s.d.). The apparent volume of distribution was 0.72 + 0.141 kg-1 (mean ± s.d.) which was larger than in healthy volunteers (P < 0.05). The total body clearance was 30.3 ± 9.4 ml kg-' h-1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P < 0.02). After cytotoxic therapy the half-life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 + 1.3 h (mean ± s.d.) (P < 0.07), and the apparent volume of distribution was reduced to 0.65 ± 0.071 kg-(mean ± s.d.) (P < 0.05) while the total body clearance increased to 52.8 + 5.5 ml kg-' h-1 (mean ± s.d.) (P < 0.01).

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Decreased half life of cyclophosphamide in patients under continual treatment

Cited by 66 publications

References 9 publications

Sustained P450 expression and prodrug activation in bolus cyclophosphamide-treated cultured tumor cells. Impact of prodrug schedule on P450 gene-directed enzyme prodrug therapy

Sustained P450 expression and prodrug activation in bolus cyclophosphamide-treated cultured tumor cells. Impact of prodrug schedule on P450 gene-directed enzyme prodrug therapy

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

Disposition of antipyrine in African patients with Hodgkin's lymphoma.

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