High-dose 7-hydroxymethotrexate: Acute toxicity and lethality in a rat model

Smeland, Eivind; Fuskevåg, Ole-Martin; Nymann, Kirsten; Svendsen, John S.; Olsen, Randi; Lindal, Sigurd; Bremnes, Roy M.; Aarbakke, Jarle

doi:10.1007/s002800050406

Cited by 52 publications

(33 citation statements)

References 46 publications

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“…This is thought to be caused by the precipitation of MTX and especially 7OH-MTX, which is highly insoluble, in kidney tubules (31,32). As shown before (16), the urinary output of MTX and 7OH-MTX in Abcc2 -/-mice was significantly increased compared with wild-type in the first 24 hours after MTX administration.…”

Section: Discussionmentioning

confidence: 62%

“…Given the increased kidney levels and urinary output of MTX and 7OH-MTX in Abcc2-deficient mice, reduced ABCC2 expression/activity may be a risk factor for kidney toxicity, which is primarily due to the precipitation of these compounds in urine (31,32). Interestingly, renal failure after high-dose MTX treatment in a patient with an ABCC2 mutation has been reported (43).…”

Section: Discussionmentioning

confidence: 99%

“…7OH-MTX -related toxicity in patients is suggested to mainly occur in the kidney, leading to renal failure (31,32). Therefore, we analyzed the kidney levels of 7OH-MTX after i.v.…”

Section: Abcc2mentioning

confidence: 99%

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Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate In vivo

Vlaming¹,

Pala

Esch³

et al. 2009

Clinical Cancer Research

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Purpose: ABCC2 (MRP2) and ABCG2 (BCRP) transport various endogenous and exogenous compounds, including many anticancer drugs, into bile, feces, and urine. We investigated the possibly overlapping roles of Abcg2 and Abcc2 in the elimination of the anticancer drug methotrexate (MTX) and its toxic metabolite 7-hydroxymethotrexate (7OH-MTX). Experimental Design: We generated and characterized Abcc2;Abcg2 -/-mice, and used these to determine the overlapping roles of Abcc2 and Abcg2 in the elimination of MTX and 7OH-MTX after i.v. administration of 50 mg/kg MTX. Results: Compared with wild-type, the plasma areas under the curve (AUC) for MTX were 1.6-fold and 2.0-fold higher in Abcg2 -/-and Abcc2 -/-mice, respectively, and 3.3-fold increased in Abcc2;Abcg2 -/-mice. The biliary excretion of MTX was 23-fold reduced in Abcc2;Abcg2-/-mice, and the MTX levels in the small intestine were dramatically decreased. Plasma levels of 7OH-MTX were not significantly altered in Abcg2 -/-mice, but the areas under the curve were 6.2-fold and even 12.4-fold increased in Abcc2 -/-and Abcc2;Abcg2 -/-mice, respectively. This indicates that Abcc2 compensates forAbcg2 deficiency but that Abcg2 can only partly compensate for Abcc2 absence. Furthermore, 21-fold decreased biliary 7OH-MTX excretion in Abcc2;Abcg2 -/-mice and substantial 7OH-MTX accumulation in the liver and kidney were seen. We additionally found that in the absence of Abcc2, Abcg2 mediated substantial urinary excretion of MTX and 7OH-MTX. Conclusions: Abcc2 and Abcg2 together are major determinants of MTX and 7OH-MTX pharmacokinetics. Variations in ABCC2 and/or ABCG2 activity due to polymorphisms or coadministered inhibitors may therefore substantially affect the therapeutic efficacy and toxicity in patients treated with MTX.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate In vivo

Vlaming¹,

Pala

Esch³

et al. 2009

Clinical Cancer Research

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“…Clinically used drugs exhibiting a major clearance pathway via AO are few, and to date, no clinically relevant DDIs resulting from AO inhibition have been recognized, despite the identification of many clinical drugs demonstrating AO inhibition in vitro (Obach et al, 2004); however, our data indicate that inhibition of alternate clearance routes (e.g., P450) for drugs also metabolized by AO may result in elevation of a circulating AO-mediated metabolite, which, importantly, could have clinical implications when metabolites exhibit pharmacologic or toxicologic activity (Smith and Obach, 2005). For example, cases of dosedependent renal toxicity associated with AO-mediated formation of a low-solubility metabolite have been reported for methotrexate (Smeland et al, 1996) and the two c-Met inhibitors SGX523 and JNJ-38877605, recently discontinued in clinical trials (Infante et al,TABLE 6 Systemic exposure of metabolites M1 and M2 after an i.p. administration of 1 (10 mg/kg) to control rats or rats pretreated with ABT, allopurinol, or allopurinol + ABT Area under the curve reported as peak area ratio analyte/IS* h, as no authentic metabolite standards were available.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity

Crouch

Morrison

Byers

et al. 2016

Drug Metabolism and Disposition

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Marketed drugs cleared by aldehyde oxidase (AO) are few, with no known clinically relevant pharmacokinetic drug interactions associated with AO inhibition, whereas cytochrome P450 (P450) inhibition or induction mediates a number of clinical drug interactions. Little attention has been given to the consequences of coadministering a P450 inhibitor with a compound metabolized by both AO and P450. Upon discovering that VU0409106 (1) was metabolized by AO (to M1) and P450 enzymes (to M4-M6), we sought to evaluate the in vivo disposition of 1 and its metabolites in rats with attenuated P450 activity. Male rats were orally pretreated with the pan-P450 inactivator, 1-aminobenzotriazole (ABT), before an i.p. dose of 1. Interestingly, the plasma area under the curve (AUC) of M1 was increased 15-fold in ABT-treated rats, indicating a metabolic shunt toward AO resulted from the drug interaction condition. The AUC of 1 also increased 7.8-fold. Accordingly, plasma clearance of 1 decreased from 53.5 to 15.3 ml/min per kilogram in ABT-pretreated rats receiving an i.v. dose of 1. Consistent with these data, M1 formation in hepatic S9 increased with NADPH-exclusion to eliminate P450 activity (50% over reactions containing NADPH). These studies reflect possible consequences of a drug interaction between P450 inhibitors and compounds cleared by both AO and P450 enzymes. Notably, increased exposure to an AO metabolite may hold clinical relevance for active metabolites or those mediating toxicity at elevated concentrations. The recent rise in clinical drug candidates metabolized by AO underscores the importance of these findings and the need for clinical studies to fully understand these risks.

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“…Smeland et al 10 found acute renal and hepatic toxicity as evidenced by severe morphological findings, during their investigations to elucidate the mechanism for Methotrexate induced renal and hepatic toxicity.…”

mentioning

confidence: 99%

Toxicity profile of anticancer drugs in acute lymphoblastic leukemia and protective role of vitamin E on these toxicities in albino rats

Roy¹,

Narayanan

2015

Int J Sci Rep

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Background: Objectives: (1) To study the spectrum of toxicity due to chemotherapy as per MCP841 protocol during the acute phase of treatment of patients with Acute Lymphoblastic Leukemia (ALL). (2) To study the same toxicities in albino rats and the protective role of vitamin E on these toxicities.Methods: This was a prospective clinical study for one year, in the department of medical oncology and paediatric oncology which was augmented by experimental animal study for 5 months using albino rats. For clinical study, patients diagnosed as ALL taking treatment as per MCP841 protocol were taken. Patients were followed up every day to detect the development of any type of adverse reactions or toxicity symptoms. Laboratory tests done during the course of chemotherapy were reviewed for any abnormality. Animal study involved 18 albino rats; rats were divided into 3 Groups; Group 1 - control (n=6), Group 2 - antileukaemic treated rats (n=6), Group 3 - antileukaemic drugs and vitamin-E treated rats (n=6). Results: In the clinical study major toxicities observed were haematological, metabolic, gastrointestinal, general infection, neurotoxicity, pancreatitis, pneumonitis and jaundice. Neurosensory toxicity presented as numbness in the extremities and hyperalgesia and myalgia. Histopathological examination of the internal organs of albino rats studied showed protection of vitamin E for the gastric toxicity, pancreatitis, cardiac toxicity, neuro toxicity and hepatic toxicity whereas there was no reduction in splenic and renal toxicities. In the case of haematological toxicity, protection was only minimal.Conclusions: The animal study revealed the protective role of vitamin E on cytostatic drug induced toxicities. Keywords: Acute lymphoblastic leukaemia (ALL), Antileukaemic drugs, Vitamin E (Vit. E), MCP841 protocol

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High-dose 7-hydroxymethotrexate: Acute toxicity and lethality in a rat model

Cited by 52 publications

References 46 publications

Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate In vivo

Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate In vivo

Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity

Toxicity profile of anticancer drugs in acute lymphoblastic leukemia and protective role of vitamin E on these toxicities in albino rats

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