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

本研究观察了大鼠生后肝脏醛氧化酶（AO）和黄嘌呤氧化酶（XO）的发育变化。AO的表达与氧化酶活性密切相关。而XO与AO的表达关系密切。AO和XO的活性中心含有钼，钼辅基对活性有影响。我们评估了Mo辅因子合成（MOCS）蛋白的发育变化。MOCS蛋白质随时间的变化而变化，并与AO和XO活性有较好的相关性。因此，AO和XO活性受酶和MOCS蛋白表达的调节。别嘌呤醇通过AO和XO代谢为一种有效的XO抑制剂羟嘌呤醇。我们通过发育变化来研究别嘌呤醇代谢的变化及其疗效。别嘌呤醇的功效被评价为XO抑制。XO活性水平由细胞质中黄嘌呤和次黄嘌呤的比率预测，根据以下公式计算：（黄嘌呤/（黄嘌呤+次黄嘌呤）] 3周龄大鼠的别嘌呤醇氧化酶活性低于6周龄大鼠（3周：1.69 nmol/60 min/mg蛋白，6周：8.93 nmol /60 min/mg蛋白）。XO活性指数RX在3周组高于6周组（3周：0.76，6周：0.56）。别嘌呤醇的疗效，XO抑制，随着年龄的增长而增加。我们评估了AO和XO对别嘌呤醇代谢的贡献。3周龄大鼠的AO代谢产物为别嘌呤醇的18.0%。6周龄大鼠AO代谢产物的含量为80.7%。AO对别嘌呤醇代谢的影响随年龄而变化。

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.