High-dose 7-hydromethotrexate: acute toxicity and lethality in a rat model.
To elucidate mechanisms for methotrexate (MTX)-induced renal and hepatic toxicity, we investigated the acute effects of bolus plus continuous infusion of up to 0.4 g/kg 7-hydroxymethotrexate (7-OH-MTX) in the rat. We demonstrate for the first time in any species the occurrence of acute lethal toxicity within a few hours after 7-OH-MTX administration. Serum concentrations of 7-OH-MTX measured at the time of death were 1.4 mM (mean), about one-half of those achieved in some patients after infusion of high-dose MTX (HD-MTX) in the clinic. The data suggest an approximate LD50 (the dose lethal to 50% of the study population) of 0.3 g/kg and a steep dose/lethality curve for 7-OH-MTX. Moreover, acute renal and hepatic toxicity occurred as evidenced by severe morphological findings and increased serum levels of creatinine and liver transaminases. In all rats subjected to continuous infusion of 7-OH-MTX, yellow microscopic precipitations were apparent in the kidney tubules. Crystallization was also seen in bile ducts of the liver in some of the rats. These results further support that the formation of 7-OH-MTX is disadvantageous and that reported attempts to prevent its formation during MTX treatment are warranted.
Smeland
E
E
Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Norway.
Fuskevåg
O M
OM
Nymann
K
K
Svendesn
J S
JS
Olsen
R
R
Lindal
S
S
Bremnes
R M
RM
Aarbakke
J
J
D000818:Animals; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000633:toxicity*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000648:ultrastructure; D007684:Kidney Tubules / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000633:toxicity; D051381:Rats; D015996:Survival Rate; D013997:Time Factors
D005493:Folic Acid Antagonists; C011864:7-hydroxymethotrexate; D008727:Methotrexate