A One-Month Repeated Oral Dose Toxicity Study of Methotrexate in Unilaterally Nephrectomized Rats

Murakami, Yoshinori; Yamazaki, Kimie; Sakauchi, Narumi; Ogasawara, Hiroyuki; Yamashita, Noriaki; Masuda, Tatsuki; Tauchi, Kiyonori

doi:10.2131/jts.23.supplementv_681

Cited by 11 publications

(11 citation statements)

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“…Moreover, the results were also consistent with a previous report using MTX-treated SD rats following unilateral nephrectomy or a sham operation (Murakami et al, 1998). Bone marrow cytology has not been included in the study of MTX-treated SD rats (Murakami et al, 1998). We showed that MTX impaired haematopoiesis not only in erythroid linage but also in myeloid linage of the bone marrow.…”

Section: Discussionsupporting

confidence: 91%

“…An earlier clinical study demonstrated that thrombocytosis was followed by thrombocytopenia as a "rebound" phenomenon in patients taking MTX (Ogston et al, 1968). Moreover, the results were also consistent with a previous report using MTX-treated SD rats following unilateral nephrectomy or a sham operation (Murakami et al, 1998). Bone marrow cytology has not been included in the study of MTX-treated SD rats (Murakami et al, 1998).…”

Section: Discussionsupporting

confidence: 85%

“…Indeed, a single intravenous injection of MTX reduces the pro/pre B-cell population in spleen tissue, where a reduction of CD90 + cells in the lymphocyte corona is observed (Zandvoort et al, 2001). Thymic atrophy has been reported in rats treated with 0.2 and 0.6 mg/ (kg·day) MTX for 28 days (Murakami et al, 1998). MTX is a potential inducer of apoptosis in isolated neutrophils and lymphocytes (Cetiner et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The dose volume was 5 ml/kg. The doses were selected on the basis of a previously reported 4-week repeated-dose oral toxicity study of unilaterally nephrectomised Sprague-Dawley (SD) rats that received MTX orally at a doses of 0.06, 0.2, or 0.6 mg/ (kg·day) (Murakami et al, 1998). Stability of MTX at 0.004 and 0.12 mg/ml was ensured for the study: MTX was sealed and stored in cold and dark conditions for 7 days and then exposed to ambient air for 4 hr (over 99% of initial values at each dose level).…”

Section: Animal Husbandry and Experimental Designmentioning

confidence: 99%

“…The major side effects of MTX treatment are the development of drug-resistant tumour cells (Fotoohi et al, 2004;Sorich et al, 2008), gastrointestinal toxicity (May et al, 1995;Vardi et al, 2008), bone marrow toxicity (Ermens et al, 1989;May et al, 1995;James et al, 2000;Belur et al, 2005), and pancytopenia (Chan et al, 2004;Cohen et al, 2005;McEwen et al, 2007) Anaemia is one of the most significant prognostic factors of MTX toxicity among patients with cancer or rheumatoid arthritis during the treatment period (Han et al, 2007;Dubsky et al, 2008). However, haematological changes along with bone marrow cytology have not been documented in rats, and limited data is available from studies using unilaterally nephrectomised rats treated with MTX that show the progression of severe anaemia in the absence of reticulocyte adaptation (Murakami et al, 1998). In this study, we determined the haematological and bone marrow toxicity in Wistar Hannover rats following a 4-week course of repeated oral administration of MTX.…”

Section: Introductionmentioning

confidence: 99%

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Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

et al. 2012

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-Anaemia is a significant prognostic factor in cancer patients receiving anticancer drugs such as methotrexate (MTX). This study focuses on the effects of toxicological changes on the hematopoietic systems in male and female Wistar Hannover rats when MTX is orally administered at a dose of 0, 0.05, 0.15, or 0.45 mg/(kg·day) for a period of 28 days. Both male and female rats receiving 0.45 mg/kg MTX showed a decrease in the haemoglobin concentration (Hb), haematocrit, and erythrocyte count. Female rats showed a decrease in mean corpuscular volume (MCV) and an increase in cell mean Hb (CHCM) in total erythrocytes, including the mature erythrocytes. These results indicate that MTX causes the production of small, mature erythrocytes that contain a high concentration of Hb. MTX reduced the number of peripheral reticulocytes but produced the cells with a large size and a high concentration of Hb, as demonstrated by the reticulocyte MCV and CHCM as well as the content of haemoglobin per reticulocyte (CHr). Consistent with these findings, bone marrow haematopoiesis was impaired by MTX, as there was a reduction in erythroid count in rats of both sexes. The number of cells of the myeloid lineage reduced in female rats, followed by a reduction in the total leukocyte and neutrophil counts in peripheral blood. Thrombocytopenia was detected in a small population of rats. These results indicate that MTX induces hyperchromic microcytic anaemia and pancytopenia, and the use of MCV and CHCM in mature erythrocytes and reticulocytes, along with the CHr, gives a better understanding of the development and nature of anaemia.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Animal Husbandry and Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

et al. 2012

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Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function

Park

et al. 2014

Clin Rheumatol

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We evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients. We enrolled 92 RA patients with normal laboratory results related to liver and kidney functions, who had received methotrexate and celecoxib concurrently over 6 months. Liver stiffness measurement (LSM) using transient elastography and ultrasonography were performed along with blood and urine tests. Estimated glomerular filtration rate (eGFR) was calculated by both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) equations. Initial eGFR represented kidney function at the time of the initiation of celecoxib. The cutoff for abnormal LSM values was adopted as 5.3 kPa. The optimal cutoff of each eGFR for abnormal LSM values was also calculated. The median age of patients was 55 years old (74 women). The median LSM was 4.4 kPa and the median eGFRs and median initial eGFRs ranged from 89 to 99 mL/min/1.73 m(2). The cumulative doses of methotrexate and celecoxib and their concurrent administration duration did not affect LSM values and eGFRs. Both eGFRs were significantly associated with LSM values. Patients with initial eGFR(CKD-EPI), initial eGFR(MDRD), and eGFR(CKD-EPI) below each optimal cutoff had significantly high risks for silent liver fibrosis (RR 9.4, 10.3, and 4.4, p < 0.001, respectively). Both initial eGFRs (CKD-EPI and MDRD) and eGFR (CKD-EPI) were significant predictors for the development of silent liver fibrosis in RA patients who had received methotrexate and celecoxib concurrently for at least 6 months.

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A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity

Blackburn

Daston

Fisher

et al. 2015

Regulatory Toxicology and Pharmacology

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A One-Month Repeated Oral Dose Toxicity Study of Methotrexate in Unilaterally Nephrectomized Rats

Cited by 11 publications

References 7 publications

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function

A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity

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