Filler G
Department of Paediatrics, Children's Hospital of Western Ontario, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Transplant Proc. 2007 May;39(4):1241-3. doi: 10.1016/j.transproceed.2007.03.049.
The metabolism of drugs in children differs from adults, although pediatric pharmacokinetic (PK) studies remain scarce. Many of the drugs are metabolized by polymorphically expressed enzymes (cytochrome P450 [CYP450]; glucuronyl transferase [GT]) and/or transported by drug transporters (ABC and SLC families). In children, there is added complexity because of the age dependency of drug metabolism. This review addresses the age dependency of drug metabolism in childhood on the basis of routine PK monitoring.
Standard pharmacokinetic studies in pediatric renal transplant recipients were analyzed to study drug-drug interactions between mycophenolic acid and cyclosporine on the one hand, and tacrolimus and sirolimus on the other hand. The exposure was compared with age. We also studied sirolimus metabolites, both by mass spectrometry as well as using human liver microsomes.
We demonstrated age dependency for MPA exposure. Independent of the concomitant medication, infants required approximately twice as much drug for the same exposure. The drug-drug interaction between sirolimus and tacrolimus demonstrated age dependency. Sirolimus metabolites showed a remarkably different pattern in children. Whereas 39-O-desmethyl sirolimus is the most prevalent metabolite in adults, we found 77.5% hydroxylated metabolites in children. Similarly, pediatric human liver microsomes produced 86.1% hydroxylated metabolites.
Our long-term objective is to develop evidence-based guidelines for age-appropriate drug dosing of all drugs commonly used during childhood and adolescence, based on pharmacokinetically/pharmacogenetically determined drug exposure to maximize therapeutic yield while minimizing toxicity. The potential need for lifelong medications warrants efforts to minimize toxicity in chronically ill pediatric patients.
儿童药物代谢与成人不同，尽管儿科药代动力学（PK）研究仍然匮乏。许多药物由多态性表达的酶（细胞色素P450 [CYP450]；葡糖醛酸转移酶 [GT]）代谢和/或由药物转运体（ABC和SLC家族）转运。在儿童中，由于药物代谢的年龄依赖性，情况更加复杂。本综述基于常规PK监测探讨儿童期药物代谢的年龄依赖性。
分析儿科肾移植受者的标准药代动力学研究，以研究霉酚酸与环孢素之间以及他克莫司与西罗莫司之间的药物相互作用。将暴露情况与年龄进行比较。我们还通过质谱以及使用人肝微粒体研究了西罗莫司的代谢产物。
我们证明了霉酚酸暴露存在年龄依赖性。与同时使用的药物无关，婴儿达到相同暴露所需的药物量约为成人的两倍。西罗莫司与他克莫司之间的药物相互作用表现出年龄依赖性。西罗莫司代谢产物在儿童中呈现出明显不同的模式。虽然39 - O - 去甲基西罗莫司是成人中最主要的代谢产物，但我们发现儿童中有77.5%的羟基化代谢产物。同样，儿科人肝微粒体产生了86.1%的羟基化代谢产物。
我们的长期目标是根据药代动力学/药物遗传学确定的药物暴露情况，制定基于证据的指南，用于儿童和青少年常用所有药物的适龄给药，以在最小化毒性的同时最大化治疗效果。对于慢性病儿科患者，由于可能需要终身用药，因此有必要努力将毒性降至最低。
