The effect of high-dose methotrexate on renal tubules as indicated by urinary lysozyme concentration.

Lysozyme was measured after 186 doses of methotrexate (MTX) to 88 patients. After 7.5% of the doses, lysozyme rose to between 2 and 19 micrograms/cc and in 3.2% it rose to between 20 and 120 micrograms/cc. These increases had no relationship to the age of the patients, their dose of MTX, the total number of times that MTX had been given, nor to rises in serum creatinine. It did correlate with the administration of aminoglycosides (a part of the supportive care of these patients) in two thirds of these cases. In patients who did not receive aminoglycosides, no urinary lysozyme concentration rose above 19 micrograms/cc, not even in the patients who became oliguric or required hemoperfusion. Most of these rises occurred early and were of 24 to 48 hour duration. The rises occurring after five days were persistent and were associated with prolonged MTX serum concentrations, suggesting that tubular damage due to MTX was the result of prolonged exposure to MTX, rather than the primary cause of kidney damage, i.e., the event causing the prolonged serum concentrations.

Chronic toxicity of methotrexate in rats: partial to complete projection of the liver by choline: Brief communication.

Methotrexate (MTX) inhibits the enzyme dihydrofolate reductase, which in turn limits the body's ability to perform transmethylation reactions. This study examined the hypothesis that the consequent deficiency of an important methylated compound, choline, may have contributed to the MTX-induced fatty change in the liver of W rats. Groups of rats were given MTX alone or MTX plus choline in varying dose combinations. All groups but one receiving the combined treatment showed a significantly lower triglyceride concentration in their livers and much less visible hepatocytic fat on histologic examination than did those given MTX alone. The protective effect of choline on the liver was dose related, the unaffected group having received a very small amount. Growth rate, survival, and hematopoietic depression due to MTX were unaltered by choline administration.

Hepatotoxicity in Wistar rats following chronic methotrexate administration: a model of human reaction.

The effects of ip administration of methotrexate (MTX) on 3-month-old male Wistar rats were studied. We administered log doses from 125 to 2,000 mug/kg, five times per week for as long as 24 months. The massive doses were promptly lethal, and most rats receiving 500 mug or more/kg died within a few weeks. Severe hematopolietic depression and ulcerative gastrointestinal lesions were observed. Truly chronic intoxication was achieved with the lesser doses. Rats in this category developed serious liver damage, namely, varying degrees of fatty metamorphosis, necrosis, atrophy of hepatic cords, and fibrosis. Hematopoietic depletion occurred in the spleen and bone marrow. Hemosiderosis was prominent in the spleen and liver. Pulmonary lesions--chiefly emphysema, occasionally fibrosis--were found less consistently. These studies demonstrated the ability of MTX to induce lesions, most consistently hepatic, in the Wistar rat, and thus have provided an animal model to evaluate protective measures.

Chronic toxicity of methotrexate in mice.

Daily (five times/week) administration of 0.25-2 mg methotrexate (MTX)/kg to 5- to 6-week-old male C57BL/6, DBA/2, and C3H mice for 12-18 months was well tolerated, apart from minimal cellular suppression in the lymphoid tissues, testes, and skin. Larger doses of MTX (3-6 mg/kg) given to 5- to 6-week-old mice produced well-known acute to subacute hematopoietic and gastrointestinal damage that leads to early death. These young mice did not develop other lesions that were described in humans after long-term MTX administration, nor was the toxicity cumulative. A large difference was observed in the ability of mice of different ages to withstand the toxic effects of MTX; 16-week-old mice were able to survive daily doses of 3-6 mg/kg up to 18 months. Histologic studies of these mice showed a more pronounced cellular depression of the lymphoid tissues, testes, and skin. Osteoporosis was also observed in these older mice that tolerated the drug for 10 months or longer, thus providing a laboratory animal model for further study of this MTX-induced lesion.

Choline antagonism of methotrexate liver toxicity in the rat.

Because of the frequent reports of hepatic toxicity associated with long-term administration of methotrexate, a rat model was developed utilizing daily methotrexate administration. This model revealed an incidence of fatty metamorphosis of over 80 percent, atrophy and necrosis of 30 percent, and fibrosis of 10 percent. Fatty liver changes did not differ substantially from control animals in those animals receiving long-term thydroxyurea, an agent which, like methotrexate, inhibits DNA synthesis but unlike methotrexate, does not impair methylation reactions. Because choline has a lipotropic effect and because its synthesis requires methylation, an attempt was made to block the liver toxicity of methotrexate by simultaneous administration of choline. Animals so treated did not show the pathologic changes in the liver characteristic of methotrexate treatment alone. Furthermore, the accumulation of triglycerides in the liver which was characteristic of methotrexate administration was markedly reduced in those animals receiving choline. These data strongly suggest that, in the rat model, methotrexate produced liver toxicity by virtue of an effect other than inhibition of DNA synthesis; and that this toxicity can be blocked without impairing methotrexate effect on bone marrow by the administration of choline, a lipotropic agent requiring methylation for its synthesis. It is suggested that these results may have implications for human therapeutic situations involving long-term administration of methotrexate.

Comparison of serum concentrations of methotrexate after various routes of administration.

Serum concentrations of methotrexate (MTX) were compared in 20 patients after administration of 15 mg/m2 MTX orally, intramuscularly, orally in divided doses, and/or intravenously. Higher and more sustained concentrations usually occurred after intramuscular administration of the drug. Approximately 50% of the patients had measurable serum concentrations 24 hours after a dose, except when the drug was given intravenously. In patients continued on MTX twice a week antimetabolic effects appeared sooner in persons with more sustained serum levels.