Phenytoin Induced Changes in Glucose and Lipid Metabolism is Related to Increased Urate Synthesis

Aim: The study was to investigate the relationship of phenytoin-associated hyperuricaemia with the hyperglycaemia and dyslipidaemia caused by phenytoin administration.

Methods: Forty-two albino Wistar rats were randomly divided into six (6) groups of 7 rats each. Group 1 animals served as the control (receiving normal saline 0.50 ml). Groups 2,3,4,5 and 6 received phenytoin, phenytoin + vitamin C, phenytoin + vitamin E, phenytoin +vitamin E +vitamin C and phenytoin + allopurinol respectively. The drugs were administered once daily for four weeks by oral intubation as follows: Phenytoin: 5 mg/kg body weight of rat, vitamin C: 1.4 mg/kg body weight of rat, Vitamin E: 10 IU/kg body weight of rat and allopurinol 5mg/kg body weight of rats. Appropriate immunoassay or spectrophotometric methods were used for analysis of fasting plasma glucose, insulin, cholesterol, triglyceride and catalase activities.

Results: Showed a significant elevation of serum uric acid following phenytoin administration (p= 0.000) that were not reversed by co-administration of antioxidant vitamins but were reduced by allopurinol administration. Serum catalase activities which were significantly depressed by phenytoin treatment were reversed by antioxidant Vitamins C, E or allopurinol. The concentration of fasting plasma glucose, insulin resistance index, total cholesterol and triglyceride were significantly increase [(59.5%: p=0.001), (87.9%: p=0.005), (35.7%: p=0.000), (34.5% p=0.027)] respectively by phenytoin administration compared to control. However, the values of these parameters were not significantly lowered by antioxidant Vitamins, but significant reduction (p=0.017) to values similar to those of normal control group were observed in the group receiving both phenytoin and allopurinol. Fasting plasma insulin levels were not significantly (16.8%: p=0.137) affected by these drug treatments. Pearson bivariate correlation analysis of data of the experimental groups and control showed significant positive correlation between uric acid and fasting plasma glucose (r=0.598, P=0.000), fasting plasma insulin (r=0.394, P=0.010), insulin resistance index (HOMAIR: r=0.551, P=0.000), total cholesterol (r=0.677, P=0.000) and triglyceride (r=0.490, P.0.001).

Conclusion: We conclude that the metabolic toxicities of phenytoin associated with impaired glucose metabolism, insulin resistance and dyslipidaemia, are related to phenytoin induced hyperuricaemia.