Mini reviewDevelopmental expression of drug metabolizing enzymes: Impact on disposition in neonates and young children
Graphical abstract
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.
Section snippets
Patterns of human drug metabolizing enzyme ontogeny
The development of highly specific antibodies to human drug metabolizing enzymes, along with the identification of specific probe substrates, has permitted the elucidation of temporal-specific enzyme expression patterns or developmental trajectories by numerous investigators [reviewed in Hines (2008)]. Although many of these studies have been conducted in vitro using human liver tissue banks, there also are instances wherein successful investigations have been completed in vivo by determining
Windows of hypervariability
Early studies by Cresteil and colleagues [reviewed in Hines (2008)], as well as others, suggested that the most substantial changes in expression of the human hepatic drug metabolizing enzymes would occur in the perinatal period. However, it also was apparent that erroneous conclusions regarding developmental expression patterns had been made by investigators developing opportunistic sample sets that represented limited time-frames during development [e.g., CYP2E1, discussed in Johnsrud et al.
Interplay between genetic variability and developmental factors in determining drug metabolism phenotype in children
As is apparent from the examples of therapeutic misadventures described in the Introduction, as well as the case reports of transient trimethylaminuria above, the underlying cause of metabolic insufficiency in children may be of genetic origin, developmental factors, or a combination of both. However, in most instances, it has been demonstrated that age usually trumps genetics in determining phenotype. CYP2D6 is an important drug metabolizing enzyme in both children and adults. CYP2D6 is a
Regulation of drug metabolizing enzyme ontogeny
Knowledge of specific mechanisms regulating drug metabolizing enzyme ontogeny is limited. There is some evidence that changes in transcription factor expression during development can have a role and in particular, HNF1α, C/EBPα, C/EBPβ, and PAR transcription factors (Ourlin et al., 1997, Edenberg, 2000, Martinez-Jimenez et al., 2005, Klick et al., 2008). However, other mechanisms likely will be involved. Vieira et al. (1996) provided evidence that changes in DNA methylation contributed to the
Predicting drug metabolism capacity in early life stages
Several physiological parameters also undergo changes during early life-stages that can have a profound impact on drug disposition [see Kearns et al. (2003) and Alcorn and McNamara (2003) for recent reviews]. Of these, anatomical and functional changes in the liver and kidney have the greatest influence on pharmacokinetics. Hepatic organogenesis begins during gestational week four and rapidly progresses with the fundamental components of the liver being formed by 13–14 weeks. By 12 weeks, the
Conclusions
Profound changes occur in the expression of many drug metabolizing enzymes during early life stages that can substantially impact response and disposition. Although ignorance of these changes has led to several therapeutic misadventures with consequent adverse effects, it is hoped greater awareness and the application of tools such as physiologically-based pharmacokinetic modeling will prevent such occurrences in the future. Further, as we gain more knowledge regarding the mechanisms regulating
Acknowledgements
Partial support for the studies described herein was provided by PHS grants CA53106 and GM081344 (RNH).
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