Dose adjustment based on the developmental changes of drug metabolic enzyme activity and their pharmacological activity.

点击翻译按钮获取中文摘要

In the present study, we observed the developmental changes of aldehyde oxidase (AO) and xanthine oxidase (XO) in postnatal rat liver. The expression of AO was closely correlated with the oxidase activity. As for XO, there was good relation to the expression of XO, as like AO. It is said that AO and XO contain molybdenum (Mo) in their active center, and then Mo cofactor effect on the activity. We evaluated the developmental changes of Mo cofactor Synthesis (MOCS) protein. There is the developmental change on MOCS protein, and we observed the good relation to AO and XO activity. Thus, the AO and XO activity are regulated by both the expression of the enzyme and MOCS protein. Allopurinol is metabolized to oxypurinol, a potent XO inhibitor, by AO and XO. We examined the change of allopurinol metabolism and their efficacy by the developmental changes. Allopurinol efficacy is evaluated as the XO inhibition. The level of XO activity was predicted from the ratio of xanthine and hypoxanthine in the cytosols, calculated according to the following equation: Ratio of xanthine formation (RX) = [(xanthine/ (xanthine + hypoxanthine)]Three weeks aged rats have lower allopurinol oxidase activity than 6 weeks aged rats (3 weeks: 1.69nmol /60 min/mg protein, 6 weeks: 8.93 nmol /60 min/mg protein). The level of RX, the index of XO activity, in 3 weeks rats was higher than that in 6 weeks rats (3 weeks: 0.76, 6 weeks: 0.56). The allopurinol efficacy, XO inhibition, was increased with age. We evaluated the contribution of allopurinol metabolism by AO and XO. AO metabolite 18.0% of allopurinol in 3 weeks aged rats. On the other hand, AO metabolite 80.7% in 6 weeks aged rats. It was observed that the contribution by AO on allopurinol metabolism changes with age.