Pharmacokinetics of N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in the rat

Lü, Hong; Chan, Kenneth K.

doi:10.1007/s00280-006-0196-7

Cited by 9 publications

(5 citation statements)

References 17 publications

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“…For 5-FU, epirubicin and cyclophosphamide (and its metabolite), the unbound fraction (fu) is moderate or high (0.2-0.9) and no major species differences have been demonstrated [31][32][33][34][35][36][37]. Therefore the fu ratio f u rat =f u human ð Þwas in the scaling set to 1 for these drugs.…”

Section: Scalingmentioning

confidence: 99%

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

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Section: Scalingmentioning

confidence: 99%

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

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“…Although the generation of CEZ has been demonstrated both in vivo and in vitro , determining the relative contribution of CEZ to CPA-induced cytotoxicity has proven difficult due to the compound’s volatility and the instability of its precursor, PM. CEZ plasma concentrations were shown to peak 5 minutes after intravenous PM administration in rats (Lu and Chan, 2006). An additional study demonstrated that following complete degradation of PM in solution, 85% of the solution’s cytotoxicity remained due to the generation and continued presence of CEZ (Chan et al , 1994).…”

Section: Introductionmentioning

confidence: 99%

Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity

Madden

Hoyer

Devine

et al. 2014

Toxicology and Applied Pharmacology

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The finite ovarian follicle reserve can be negatively impacted by chemical exposures including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4 days before being exposed once to PM (10 or 30 μM). Following eight additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P < 0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60 μM) exposure destroyed all stage follicles after 4 days (P < 0.05). VC from nearby wells depleted primordial follicles after 4 days (P < 0.05), temporarily reduced secondary follicle number after 2 days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.

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“…However, PM can undergo another spontaneous reaction to form the volatile, cytotoxic metabolite chloroethylaziridine (CEZ) , which, due to its higher cell permeability (Hata and Watanabe, 1994) and longer half-life compared to PM (Lu and Chan, 2006), may also contribute to CPA-induced ovotoxicity .…”

Section: Published In the Book Ovarian Toxicology As A Subsection Of mentioning

confidence: 99%

“…Although the generation of CEZ has been demonstrated both in vivo and in vitro, determining the relative contribution of CEZ to CPAinduced cytotoxicity has proven difficult due to the compound's volatility and the instability of its precursor, PM. CEZ plasma concentrations were shown to peak 5 minutes after intravenous PM administration in rats (Lu and Chan, 2006). An additional study demonstrated that following complete degradation of PM in solution, 85% of the solution's cytotoxicity remained due to the generation and continued presence of CEZ (Chan et al, 1994).…”

Section: Birth Puberty Menopausementioning

confidence: 99%

Investigation of mechanisms of follicle depletion and the ovarian protective response to ovotoxicant exposure

Madden

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The finite ovarian follicle reserve can be negatively impacted by chemical exposures including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PM-induced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4 days before being exposed once to PM (10 or 30 µM). Following eight 25 additional days in culture, relative to control (1% DMSO), PM had no impact on primordial, small primary or large primary follicle number, but both PM concentrations induced secondary follicle depletion (P < 0.05). Interestingly, a reduction in follicle number in the control-treated ovaries was observed. Thus, the involvement of a volatile, cytotoxic PM metabolite (VC) in PM-induced ovotoxicity was explored in cultured rat ovaries, with control ovaries physically separated from PM-treated ovaries during culture. Direct PM (60 µM) exposure destroyed all stage follicles after 4 days (P < 0.05). VC from nearby wells depleted primordial follicles after 4 days (P < 0.05), temporarily reduced secondary follicle number after 2 days, and did not impact other stage follicles at any other time point. VC was determined to spontaneously liberate from PM, which could contribute to degradation of PM during storage. Taken together, this study demonstrates that PM and VC are ovotoxicants, with different follicular targets, and that the VC may be a major player during PM-induced ovotoxicity observed in cancer survivors.

show abstract

Pharmacokinetics of N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in the rat

Cited by 9 publications

References 17 publications

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity

Investigation of mechanisms of follicle depletion and the ovarian protective response to ovotoxicant exposure

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