Pharmacokinetics, metabolic activation, and lung toxicity of cyclophosphamide in C57B16 and ICR mice

Kanekal, Sarathchandra; Fraiser, Lucy; Kehrer, James P.

doi:10.1016/0041-008x(92)90089-b

Cited by 22 publications

(8 citation statements)

References 14 publications

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“…Because CYP is a prodrug that is metabolized by the liver to produce the bladder irritant acrolein, which is responsible for the occurrence of cystitis both in rodents and humans (18,32), we interpret the present data as supporting cross-organ sensitization following bladder inflammation. Other reported adverse effects of CYP in mice are damage of hemopoietic and lymphoid organs (3,21), alopecia (30), and, at high doses, lung and cardiac toxicity (21,30). No further evidence for alterations in other organs has been reported thus far.…”

Section: Discussionmentioning

confidence: 92%

Cystitis increases colorectal afferent sensitivity in the mouse

Brumovsky¹,

Feng²,

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Studies in humans and rodents suggest that colon inflammation promotes urinary bladder hypersensitivity and, conversely, that cystitis contributes to colon hypersensitivity, events referred to as cross-organ sensitization. To investigate a potential peripheral mechanism, we examined whether cystitis alters the sensitivity of pelvic nerve colorectal afferents. Male C57BL/6 mice were treated with cyclophosphamide (CYP) or saline, and the mechanosensitive properties of single afferent fibers innervating the colorectum were studied with an in vitro preparation. In addition, mechanosensitive receptive endings were exposed to an inflammatory soup (IS) to study sensitization. Urinary bladder mechanosensitive afferents were also tested. We found that baseline responses of stretch-sensitive colorectal afferents did not differ between treatment groups. Whereas IS excited a proportion of colorectal afferents CYP treatment did not alter the magnitude of this response. However, the number of stretch-sensitive fibers excited by IS was increased relative to saline-treated mice. Responses to IS were not altered by CYP treatment, but the proportion of IS-responsive fibers was increased relative to saline-treated mice. In bladder, IS application increased responses of muscular afferents to stretch, although no differences were detected between saline- and CYP-treated mice. In contrast, their chemosensitivity to IS was decreased in the CYP-treated group. Histological examination revealed no changes in colorectum and modest edema and infiltration in the urinary bladder of CYP-treated mice. In conclusion, CYP treatment increased mechanical sensitivity of colorectal muscular afferents and increased the proportion of chemosensitive colorectal afferents. These data support a peripheral contribution to cross-organ sensitization of pelvic organs.

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Section: Discussionmentioning

confidence: 92%

Cystitis increases colorectal afferent sensitivity in the mouse

Brumovsky¹,

Feng²,

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The metabolism of cyclophosphamide appears to be very similar in all species (Madle et al, 1986). The pharmacokinetics of the parent compound, and the tissue distribution of the toxic metabolities vary somewhat between species, and even between different strains of mice (Madle et al, 1986;Kanekal et al, 1992), which may contribute to the higher dose required to produce significant effects in mice. However, one of the most likely sources of variation, both between rats and mice, and between different strains of mice, is the intrinsic sensitivity of the bladder to acrolein, which appears to be related to the tissue levels of glutathione , 1993.…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide cystitis in mice: Behavioural characterisation and correlation with bladder inflammation

Olivar

Laird

1999

European Journal of Pain

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The generation of transgenic 'knock-out' mice which lack genes relevant to pain is becoming increasing common. However, only one visceral pain model, the writhing test, is available in mice. The aim of this study was to adapt cyclophosphamide cystitis, a model of inflammatory visceral pain described in rats, for use in mice, and to characterise its behavioural effects. The toxic metabolites of systemically-administered cyclophosphamide are excreted in the urine, and induce bladder inflammation. We compared the effects of cyclophosphamide (100 and 300 mg/kg i.p., 4 h survival period) and vehicle (saline) in male mice on spontaneous behaviour (4 h continuous video-tape, and a 5-min Open Field test after 4 h). Involvement of the urinary bladder and other abdominal tissues was assessed by macroscopic examination and measurement of Evan's Blue plasma extravasation. Cyclophosphamide (300 mg/kg) produced significant changes in behaviour, including 22 +/- 6 min of 'crises' of visceral pain-related behaviour and a 53% reduction in activity, and also induced haemorrhage and substantial plasma extravasation in the bladder, but no change in other abdominal tissues. We conclude that cyclophosphamide cystitis has many advantages as a model of sub-acute, inflammatory visceral pain in mice. It does not require surgery or intubation, and we have found it to produce consistent, reproducible and quantifiable behavioural changes, which are significantly correlated with the degree of bladder inflammation in the absence of inflammation of other abdominal tissues. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

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“…Cyclophosphamide, a widely used cytotoxic and immunosuppressive drug, is toxic to the lungs of humans and animals, producing fatal pulmonary fibrosis [2,4,5,14,25]. Although the toxic effects of CP have been reported, there are no time course studies describing the early pulmonary injury.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that administration of cyclophosphamide (CP), an antineoplastic and immunosuppressive drug, is associated with the development of lung injury that appears as sclerosing alveolitis and diffuse interstitial fibrosis [2,4,5,14,25]. The pathogenesis of CP-induced lung injury has been investigated but not completely explored.…”

Section: Introductionmentioning

confidence: 99%

Cyclophosphamide induced early biochemical changes in lung lavage fluid and alterations in lavage cell function

Venkatesan

Chandrakasan

1994

Lung

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The present investigation evaluated the changes in bronchoalveolar lavage fluid (BALF) biochemical constituents and indices of bronchoalveolar lavage cell functions to detect early lung injury in rats following intraperitoneal administration of cyclophosphamide (CP). Rats were exposed to a single intraperitoneal injection of CP (200 or 300 mg/kg body weight). Experimental and control rats were sacrificed at various time intervals (2, 3, 5, 7, 11, 21, and 42 days after cessation of exposure), and lung lavage was performed to examine several markers of lung injury. Biochemical analyses revealed dose-related increases in BALF angiotensin converting enzyme activity, total protein, lactate, lactate dehydrogenase, and N-acetyl-beta-D-glucosaminidase (NAG) levels on days 2, 3, 5, 7, and dose-related increases in albumin, alkaline phosphatase, acid phosphatase, and lipid peroxidation on days 2, 3, 5, 7, and 11 after CP treatment. In contrast, reduced levels of ascorbic acid and glutathione (GSH) content were observed in lung lavage fluid. We also examined bronchoalveolar lavage cells for acid hydrolases (acid phosphatase, beta-glucuronidase, NAG) and GSH content. Activity of acid hydrolases was slightly elevated on day 2 and peaked on days 3, 5, and 7. However, lavage cell GSH content was decreased. Thus, measurements of pulmonary changes by analyzing lavage fluid and lavage cell functions seems to be a useful marker for assessing the early onset and development of CP-induced lung injury.

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Pharmacokinetics, metabolic activation, and lung toxicity of cyclophosphamide in C57B16 and ICR mice

Cited by 22 publications

References 14 publications

Cystitis increases colorectal afferent sensitivity in the mouse

Cystitis increases colorectal afferent sensitivity in the mouse

Cyclophosphamide cystitis in mice: Behavioural characterisation and correlation with bladder inflammation

Cyclophosphamide induced early biochemical changes in lung lavage fluid and alterations in lavage cell function

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