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 dietary admixture produced a dose-related lowering of reticulocytes and leucocytes. Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg. The potential mechanisms of these effects were investigated by comparing the responses in groups of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide. Subsets of these groups were co-treated subcutaneously with folinic acid or with a vitamin B1, B6, B12 complex. Subsets of control and 300 mg/kg groups were maintained on a 20-25% feed restriction 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 animals. Plasma and liver alanine aminotransferase (ALT) and plasma aspartate 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. Plasma glucose, triglycerides, and unsaturated and total iron binding capacities were decreased, while plasma iron levels tended to increase, mainly at the high dose. Vitamin supplementation prevented a decrease in reticulocyte counts at 300 mg/kg. Bidisomide increased urinary formimino-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 lowered at both dose levels and in feed-restricted animals. However, the relative liver weights were unaffected. Thymidine kinase and thymidylate 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 parameters are considered to result mainly from nutritional restrictions. Changes in hematologic parameters appear to be related to the combination of decreased feed consumption (leukocytes) and decreased availability or utilization of folates (reticulocytes). This alteration, however, did not affect DNA synthesis in bone marrow. The prevention by folinic 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.
Vandenberghe
Y
Y
Department of Product Safety, Searle European Development Centre, Mont-St-Guibert, Belgium.
Masson
M
M
Palate
B
B
Roba
J
J
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity*; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D004247:DNA / Q000378:metabolism; D003857:Deoxyuridine / Q000037:antagonists & inhibitors; D004032:Diet; D004435:Eating / Q000187:drug effects; D005269:Femur / Q000166:cytology / Q000187:drug effects; D005508:Food Deprivation; D005565:Formiminoglutamic Acid / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D002955:Leucovorin / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008764:Methylmalonic Acid / Q000652:urine; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013654:Taurine / Q000652:urine; D014803:Vitamin B Complex / Q000008:administration & dosage* / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D000931:Antidotes; D010880:Piperidines; D014803:Vitamin B Complex; D013654:Taurine; C061991:bidisomide; D005565:Formiminoglutamic Acid; D008764:Methylmalonic Acid; D004247:DNA; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002955:Leucovorin; D003857:Deoxyuridine