Developmental expression of drug metabolizing enzymes: Impact on disposition in neonates and young children

Abstract

Profound changes in drug metabolizing enzyme expression occurs during development that impacts drug efficacy and the risk of adverse events in the neonate and young child. A review of our current knowledge suggests individual hepatic drug metabolizing enzymes can be categorized into one of three classes based on developmental trajectories. The time frame for the perinatal changes observed for both Class 1 and Class 3 enzymes varies considerably between different enzymes. However, for a given enzyme, significant interindividual variation is observed in the timing of the perinatal changes, creating windows of hypervariability. Genetic variation clearly impacts drug disposition in children. However, developmental factors can dominate pharmacogenetic factors. Thus, a major challenge in applying pharmacogenomics to improve pediatric drug safety is determining at what age functional genetic variants identified in adults become a major determinant of expression in children. Developmental and genetic data on drug metabolizing enzyme ontogeny, as well as age-dependent changes in other physiological factors impacting drug disposition, can be integrated into physiologically-based pharmacokinetic models. Such models have proven useful in predicting the range of expected metabolic capacities at a given age.

Introduction

Science and medicine have known for decades that one cannot treat children as small adults. This principle was elegantly stated by Abraham Jocobi in his presidential address to the American Pediatric Society in 1889; “Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but..it has its own independent range and horizon…” (Halpern, 1988). Yet, ignorance of that lesson has led to several therapeutic misadventures that unfortunately have resulted in unanticipated morbidity and mortality in pediatric patients. In the 1950s, children were treated with the antibiotic, chloramphenicol, using doses simply extrapolated from adult therapeutic levels based on body weight. Numerous children suffered from symptoms of emesis, abnormal respiration, cyanosis, and cardiovascular collapse, referred to as the “gray baby syndrome.” Death also occurred in some instances. Subsequent investigations revealed that affected children were incapable of effectively metabolizing the antibiotic to its glucuronide, resulting in excessive levels of the active drug and mitochondrial toxicity. However, this was not due to any genetic deficiency, but rather to immature levels of the UDP glucuronosyltransferase enzyme responsible for chloramphenicol transformation (Weiss et al., 1960). Nearly 20 years later, there were reports of a gasping syndrome, largely in premature infants, that was eventually traced back to the use of benzyl alcohol as a preservative in intravenous fluids. The levels of benzyl alcohol used in these preparations were predicted to be safe based on adult data. However, because of immature levels of glycine N-acetyltransferase, toxicity and in some cases, death occurred in several infants (Gershanik et al., 1982). More recently, the use of cisapride to control gastric reflux in neonates was shown to result in drug-induced long QT syndrome. The major pathway for cisapride oxidative metabolism and inactivation is through CYP3A4. Drug–drug interactions observed in adults on multiple CYP3A4-dependent therapeutics had previously led FDA to issue a black-box label warning for cisapride, but its use continued for treatment of gastric reflux in many premature neonates. However, toxicity was subsequently observed in some patients independent of any drug–drug interaction. The observed toxicity was demonstrated to result from the incomplete transition from CYP3A7, the dominant CYP3A enzyme in the fetus, to CYP3A4 during the perinatal period. CYP3A7 is largely incapable of metabolizing cisapride, thus leading to toxic levels of the drug (Pearce et al., 2001). These observations led to the voluntary withdrawal of cisapride from the market.

All three of these examples of therapeutic misadventures resulted from our ignorance of human drug metabolizing enzyme ontogeny. One might ask why these adverse outcomes were not predicted by preclinical studies in animal models. However, it is now widely recognized that many of the cytochromes P450 and other enzymes important for drug metabolism arose post speciation and as a result, exhibit species-specific substrate specificities. Even some enzymes with apparent true orthologues exhibit species-specific mechanisms of regulation, e.g., FMO3 (Klick et al., 2008). This recognition was the impetus for numerous studies over the past two decades to better characterize human drug metabolism enzyme ontogeny and thereby improve our ability to better predict and avoid adverse reactions in children.