EFFECT OF FOLATE SUPPLEMENTATION ON CLINICAL-CHEMISTRY AND HEMATOLOGIC CHANGES RELATED TO BIDISOMIDE ADMINISTRATION IN THE RAT

In a chronic toxicity study in the rat, bidisomide administered as a d ietary admixture produced a dose-related lowering of reticulocytes and leucocytes(1). Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg(1). The potential mechanisms of these effects were investigated by comparing the responses in group s of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide. Subsets of these groups were co-treated subcuta neously with folinic acid or with a vitamin B1, B6, B12 complex. Subse ts of control and 300 mg/kg groups were maintained on a 20-25% feed re striction regimen for 3 months, to mimic the depression in body weight gain observed in animals receiving 1200 mg/kg. Body weight gains were significantly reduced at 1200 mg/kg and in all feed-restricted animal s. Plasma and liver alanine aminotransferase (ALT) and plasma aspartat e aminotransferase (AST) levels were also reduced at this dose level. At 300 mg/kg, plasma transaminases, glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities were increased. These changes were prevented in animals receiving folinic acid supplementation. Pla sma glucose, triglycerides, and unsaturated and total iron binding cap acities were decreased, while plasma iron levels tended to increase, m ainly at the high dose. Vitamin supplementation prevented a decrease i n reticulocyte counts at 300 mg/kg. Bidisomide increased urinary formi mino-glutamic acid (FIGLU) excretion but did not affect methylmalonic acid (MMA) or taurine excretion. The effect on FIGLU at 1200 mg/kg was prevented by folinic acid co-treatment. Absolute liver weight was low ered at both dose levels and in feed-restricted animals. However, the relative liver weights were unaffected. Thymidine kinase and thymidyla te synthase activity of the bone marrow cells were not altered by the bidisomide treatment. Except for the increase in plasma transaminase, GLDH and SDH levels at 300 mg/kg, changes in clinical chemistry parame ters are considered to result mainly from nutritional restrictions. Ch anges in hematologic parameters appear to be related to the combinatio n of decreased feed consumption (leukocytes) and decreased availabilit y or utilization of folates (reticulocytes). This alteration, however, did not affect DNA synthesis in bone marrow. The prevention by folini c acid, but not by feed restriction, of the elevation of liver enzymes at 300 mg/kg is an intriguing, yet unexplained finding. There was no evidence that bidisomide affected B6 and B12 availability.