Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates
Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates
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DOI：
10.1080/0803525051002952
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发表时间：
2005-09-01
期刊：
影响因子：
3.8
通讯作者：
Tibboel, D
中科院分区：
文献类型：
--
作者：
Allegaert, K;De Hoon, J;Tibboel, D
背景资料：在婴儿期观察到药物清除和代谢的主要变化，部分基于各种代谢途径的个体发育调节。由于扑热息痛为研究UGT（1A 6）活性提供了良好的底物，因此在反复给予丙扑热息痛的新生儿中测定了丙扑热息痛的尿液代谢物。研究方法：在丙帕他莫重复给药期间，测定新生儿尿样中对乙酰氨基酚葡糖苷酸（APAP-G）、硫酸对乙酰氨基酚（APAP-S）和游离对乙酰氨基酚。使用斯皮尔曼秩和线性多元回归（MedCalc（R），Mariakerke，比利时）研究出生后年龄、受孕后年龄和重复给药对APAP-G对总体尿液对乙酰氨基酚（APAP-G + APAP-S +游离对乙酰氨基酚）消除的相对贡献（G/T比）的影响。结果：23例新生儿共采集标本147份。摩尔中位G/T比为14%（范围1-53）。除G/T比值随出生后体重增加而增加外，（p < 0.0001）和产后年龄（p < 0.01），重复给药（p < 0.01）也与G/T比值增加相关，重复给药仍显著（p < 0.01）在多元回归模型中校正出生后和受孕后年龄后。在新生儿中记录了UGT活性个体发育与对乙酰氨基酚总体消除的主要差异。除了出生后和受孕后的年龄，重复给药对UGT活性的显着影响被记录。
Background: Major changes in drug clearance and metabolism are observed during infancy, in part based on ontogenic regulation of various metabolic pathways. Since paracetamol provides a good substrate to study UGT (1A6) activity, urinary metabolites of propacetamol were determined in neonates in whom propacetamol was repeatedly administered. Methods: Paracetamol glucuronide (APAP-G), paracetamol sulphate (APAP-S) and free paracetamol were determined in urine samples of neonates during repeated administration of propacetamol. Spearman rank and linear multiple regression (MedCalc(R), Mariakerke, Belgium) were used to study the effect of postnatal age, of postconceptional age and of repeated administration on the relative contribution of APAP-G to overall urine paracetamol (APAP-G + APAP-S + free paracetamol) elimination (G/T ratio). Results: 147 samples were collected in 23 neonates. Molar median G/T ratio was 14% (range 1-53). Besides increasing G/T ratio with increasing postnatal (p < 0.0001) and postconceptional age (p < 0.01), repeated administration (p < 0.01) also correlated with an increasing G/T ratio, and repeated administration remained significant (p < 0.01) after correction of postnatal and postconceptional age in a multiple regression model.Conclusion: Major variability in the ontogeny of UGT activity to overall elimination of paracetamol was documented in neonates. Besides postnatal and postconceptional age, a significant effect of repeated administration on UGT activity was documented.