de Wildt S N, Kearns G L, Leeder J S, van den Anker J N
Department of Pediatrics, Sophia Children's Hospital, Rotterdam, The Netherlands.
Clin Pharmacokinet. 1999 Dec;37(6):485-505. doi: 10.2165/00003088-199937060-00004.
The maturation of organ systems during fetal life and childhood exerts a profound effect on drug disposition. The maturation of drug-metabolising enzymes is probably the predominant factor accounting for age-associated changes in non-renal drug clearance. The group of drug-metabolising enzymes most studied are the cytochrome P450 (CYP) superfamily. The CYP3A subfamily is the most abundant group of CYP enzymes in the liver and consists of at least 3 isoforms: CYP3A4, 3A5 and 3A7. Many drugs are mainly metabolised by the CYP3A subfamily. Therefore, maturational changes in CYP3A ontogeny may impact on the clinical pharmacokinetics of these drugs. CYP3A4 is the most abundantly expressed CYP and accounts for approximately 30 to 40% of the total CYPcontent in human adult liver and small intestine. CYP3A5 is 83% homologous to CYP3A4, is expressed at a much lower level than CYP3A4 in the liver, but is the main CYP3A isoform in the kidney. CYP3A7 is the major CYP isoform detected in human embryonic, fetal and newborn liver, but is also detected in adult liver, although at a much lower level than CYP3A4. Substrate specificity for the individual isoforms has not been fully elucidated. Because of large interindividual differences in CYP3A4 and 3A5 expression and activity, genetic polymorphisms have been suggested. However, although some gene mutations have been identified, the impact of these mutations on the pharmacokinetics of CYP3A substrates has to be established. Ontogeny of CYP3A activity has been studied in vitro and in vivo. CYP3A7 activity is high during embryonic and fetal life and decreases rapidly during the first week of life. Conversely, CYP3A4 is very low before birth but increases rapidly thereafter, reaching 50% of adult levels between 6 and 12 months of age. During infancy, CYP3A4 activity appears to be slightly higher than that of adults. Large interindividual variations in CYP3A5 expression and activity were observed during all stages of development, but no apparent developmental pattern of CYP3A5 activity has been identified to date. Profound changes occur in the activity of CYP3A isoforms during all stages of development. These changes have, in many instances, proven to be of clinical significance when treatment involves drugs that are substrates, inhibitors or inducers of CYP3A. Investigators and clinicians should consider the impact of ontogeny on CYP3A in both pharmacokinetic study design and data interpretation, as well as when prescribing drugs to children.
胎儿期和儿童期器官系统的成熟对药物处置有着深远影响。药物代谢酶的成熟可能是导致非肾性药物清除率随年龄变化的主要因素。研究最多的药物代谢酶组是细胞色素P450（CYP）超家族。CYP3A亚家族是肝脏中最丰富的CYP酶组，至少由3种同工型组成：CYP3A4、3A5和3A7。许多药物主要由CYP3A亚家族代谢。因此，CYP3A个体发生的成熟变化可能会影响这些药物的临床药代动力学。CYP3A4是表达最丰富的CYP，约占成人肝脏和小肠中CYP总量的30%至40%。CYP3A5与CYP3A4有83%的同源性，在肝脏中的表达水平远低于CYP3A4，但却是肾脏中主要的CYP3A同工型。CYP3A7是在人类胚胎、胎儿和新生儿肝脏中检测到的主要CYP同工型，但在成人肝脏中也能检测到，不过其水平远低于CYP3A4。各个同工型的底物特异性尚未完全阐明。由于CYP3A4和3A5的表达和活性存在较大的个体差异，因此有人提出存在基因多态性。然而，尽管已经鉴定出一些基因突变，但这些突变对CYP3A底物药代动力学的影响仍有待确定。已经在体外和体内研究了CYP3A活性的个体发生。CYP3A7活性在胚胎期和胎儿期较高，在出生后的第一周迅速下降。相反，CYP3A4在出生前非常低，但此后迅速增加，在6至12个月大时达到成人水平的50%。在婴儿期，CYP3A4活性似乎略高于成人。在发育的各个阶段都观察到CYP3A5表达和活性存在较大的个体差异，但迄今为止尚未发现CYP3A5活性明显的发育模式。在发育的各个阶段，CYP3A同工型的活性都会发生深刻变化。在许多情况下，当治疗涉及CYP3A的底物、抑制剂或诱导剂药物时，这些变化已被证明具有临床意义。研究人员和临床医生在药代动力学研究设计和数据解释以及给儿童开药时，都应考虑个体发生对CYP3A的影响。
