|Year : 2017 | Volume
| Issue : 1 | Page : 115-122
Developmental pattern of hepatic drug-metabolizing enzymes in pediatric population and its role in optimal drug treatment
Sunitha Kodidela1, S Suresh Kumar2, Chakradhara Rao Satyanarayana Uppugunduri3
1 Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Pharmacology, Karuna Medical College, Palakkad, Kerala, India
3 Department of Paediatrics, CANSEARCH Research Laboratory, University of Geneva, Geneva, Switzerland
|Date of Web Publication||16-Jun-2017|
Chakradhara Rao Satyanarayana Uppugunduri
Department of Paediatrics, CANSEARCH Research Laboratory, University of Geneva, Geneva
Source of Support: None, Conflict of Interest: None
Pediatric pharmacokinetics (PK) and pharmacodynamics (PD) differ from adults in multiple aspects. The extrapolation of PK/PD data from adults to children is not always simple because children are not small adults. Differential development of metabolic enzymes in children affects both PK and PD of a drug. Thus, the study of the developmental patterns of drug-metabolizing enzymes is essential to establish the PK and PD profile of drugs in the pediatric population. Further, these patterns may also aid to establish models for appropriate extrapolation of adult data for any newer drugs. We conducted a literature search on PubMed Central, Medline database, and Google Scholar with relevant search terms to obtain articles for this narrative review. The research on developing pattern of drug metabolizing enzymes is still evolving. This review presents an overview of the existing literature on developmental patterns of key metabolic enzymes in children. Greater emphasis needs to be given to study developmental pattern of metabolic enzymes as it not only helps drug development but also to optimize drug therapy in children.
Keywords: Adults, adverse drug reaction, children, dose, metabolism, ontogeny, pediatric population, pharmacokinetics
|How to cite this article:|
Kodidela S, Kumar S S, Uppugunduri CR. Developmental pattern of hepatic drug-metabolizing enzymes in pediatric population and its role in optimal drug treatment. Arch Med Health Sci 2017;5:115-22
|How to cite this URL:|
Kodidela S, Kumar S S, Uppugunduri CR. Developmental pattern of hepatic drug-metabolizing enzymes in pediatric population and its role in optimal drug treatment. Arch Med Health Sci [serial online] 2017 [cited 2022 May 19];5:115-22. Available from: https://www.amhsjournal.org/text.asp?2017/5/1/115/208204
| Introduction|| |
Developmental changes in the expression of drug-metabolizing enzymes can profoundly affect the drug efficacy and safety, especially in the pediatric population. Children are not “small adults” with respect to drug therapy. However, overlooking this fact has led to several therapeutic failures, for example, the occurrence of “gray baby syndrome” in children who were treated with an antibiotic, chloramphenicol, using doses directly extrapolated from adult doses based on body weight. The affected had immature uridine 5′-diphospho-glucuronosyltransferase (UGT) to metabolize chloramphenicol efficiently causing mitochondrial toxicity due to higher plasma levels of the active drug. However, drug-metabolizing capacities are not consistent in children, as they exhibit increased capacity for sulfate conjugation early in life resulting in resistance to acetaminophen toxicity. Another example is UGT family member UGT2B7 which is immature at birth and in neonates <10 days of age. Thus, they require about a 25% of body weight correction in their morphine doses compared to infants to exhibit similar plasma levels. However, in practice, often children are administered with doses similar to that of adults to achieve comparable therapeutic levels.
Adverse drug reactions (ADRs) in children represent a significant public health concern. A meta-analysis of pediatric ADRs concluded that 2.1% of admissions were due to ADRs, of which 39% were severe. These estimates might not reflect the real scenario of ADRs as there are no standard reporting systems and the available primary data are derived from assessments conducted in individual pediatric hospitals. Several regulations such as European Union's Paediatric Regulation (2007) and the Best Pharmaceuticals for Children Act (last amended 2012) of the Food and Drug Administration have emphasized the need to progress further into translational research for drug use in children., Drug disposition in the pediatric population is influenced by functional changes in multiple organs and organ systems, the ratio of the liver to body mass, changes in body composition, the relative size of the skin surface area, and maturation of metabolizing enzymes. Safe and effective treatment of children requires a fundamental understanding of the pharmacokinetics (PK) and dynamics of medicines in their dynamically developing systems.
This review presents an overview of the ontogeny of drug-metabolizing enzymes (DMEs) that are crucial in determining therapeutic dosing in children. We conducted a literature search on PubMed Central, Medline database, and Google Scholar. The combination of the following search term categories: “Pediatric population,” “ontogeny,” “enzyme development,” “TDM,” “children,” “CYP450,” “pharmacokinetics,” and “adverse reactions” were used to obtain relevant articles for this narrative review.
The term pediatric population extends from the very small preterm newborn infants through to childhood and adolescents  as depicted in [Table 1].
| Developmental Pattern of Human Drug-metabolizing Enzymes|| |
The development of highly specific antibodies toward human DMEs, along with the identification of specific probe substrates, has permitted the elucidation of temporal-specific enzyme expression patterns or developmental trajectories  [Table 2].
Class I enzymes
These are expressed at their highest levels in the fetus during the first trimester, and expression levels either decrease or remain elevated during gestation. These are active toward endogenous substrates.
Class II enzymes
These express at relatively constant levels throughout gestation and in adulthood. Their expression may vary modestly within the 1st year after birth. For example, CYP2B6 and CYP2C19.
Class III enzymes
The expression of most of these enzymes reaches to adult levels from within a few weeks to 1 or 2 years, after birth (e.g., CYP1A2 and CYP3A4). However, for a few of the Class III enzymes (e.g. Flavin-containing monooxygenase 3 and CYP2C9), adult expression levels are not observed until post puberty.
Drugs undergo biotransformation through Phase I and II reactions. Phase I reactions are catalyzed by cytochrome P450 (CYP450) family and Phase II are by UGTs, sulfotransferase (SULTs), glutathione-S-transferase (GSTs), and N-acetyltransferase families. Isoenzymes within a family mature at distinct rates during the first several years of life.
| Ontogeny of Phase I Drug-metabolizing Enzymes and Adverse Drug Reactions|| |
Phase I reactions include oxidation, reduction, and hydrolysis catalyzed by CYP450 superfamily of enzymes.
| Cytochrome P450 Superfamily|| |
CYP isoenzymes are heme-containing proteins that catalyze the metabolism of several lipophilic endogenous (e.g., steroids, fat-soluble vitamins, etc.) and exogenous compounds (e.g., drugs). Total CYP450 content in fetal liver is 30%–60% of adult values and reaches 100% adult levels during the first 10 years of life. Human CYP450 superfamily members are encoded by 59 functional genes, divided into 18 families and 42 subfamilies (list available at http://drnelson.uthsc.edu/human.P450.table.html). CYP450 1–4 families are mainly involved in xenobiotic metabolism.
Cytochrome P450 1A1
It is a crucial enzyme involved in the metabolic activation of polycyclic aromatic hydrocarbons to toxic metabolites in the lung. Induction of CYP1A1 expression occurs upon exposure to polycyclic aromatic hydrocarbons from cigarette smoke. CYP1A1 is neither inducible nor constitutively expressed in adult human liver. However, the presence or absence of CYP1A family members in the human fetal liver is debatable.
Cytochrome P450 1A2
CYP1A2 is involved in caffeine and theophylline metabolism, and its ontogeny can be explained by imipramine metabolism. The major metabolite of imipramine generated in vitro by adult liver microsomes is the demethylated derivative. The formation of desipramine by liver microsomes is very low when performed with fetal preparations and accounts for no more than 3%–4% of the adult activity. The rate of demethylation begins to rise in the group of infants aged 8–28 days and progressively increases to reach the adult levels in children aged 1 year or more. Children also require higher doses of theophylline to maintain the concentration in the therapeutic range.
Dietary exposure influences the expression of the CYP1A2 enzyme. Studies have reported the rate of expression of CYP1A2 to be faster in formula milk-fed infants than in breast milk-fed infants. This could be because of inhibition or repression of the postnatal maturation process of CYP450-mediated caffeine metabolism by some components of human milk (free fatty acid, lipase activity, or other factors).
Cytochrome P450 2A subfamily
CYP2A family consists of CYP2A6, CYP2A7, and 2A13. None of the CYP2A enzymes appear to be expressed in fetal liver.CYP2A6 mRNA, protein, and activity levels reach adult levels by 1 year. CYP2A6 and CYP2A13 were readily detectable in seven of eight human fetal nasal mucosa samples from infants of 13 to 18 weeks, suggesting that CYP2A6/2A13 expression would continue to increase from the third trimester. Expression of CYP2A13 mRNA was found to be at the highest level in the nasal mucosa, followed by lung and trachea  implicating the role of CYP2A13 in xenobiotic toxicity and tobacco-related carcinogenesis in the human respiratory tract.
Cytochrome P450 2C subfamily
This subfamily consists of CYP2C8, CYP2C18, CYP2C9, and CYP2C19. Among these, CYP2C9 and CYP2C19 are most abundant in adults liver, and ontogeny of CYP2C8 and CYP2C18 is not well known. Substrates of CYP2C9 are warfarin, phenytoin, diclofenac, ibuprofen, tolbutamide, losartan, and indomethacin. CYP2C19 substrates include mephenytoin, escitalopram, and most proton-pump inhibitors such as omeprazole and lansoprazole that are commonly used in children.
A comparison of relative CYP2C9 and CYP2C19 expression levels in individual samples shows that CYP2C19 is the dominant CYP2C enzyme at the prenatal period with a transition to CYP2C9 as the dominant postnatal enzyme around birth. CYP2C9 activity progressively reaches approximately 30% of adult values during the gestational period. CYP2C9 protein and activity level are less variable between 5 months and 18 years. Ontogeny of CYP2C9 was explained with the use of phenytoin where its half-life was high in preterm infants (75 h) compared to term infants <1 week after birth (20 h) or term infants aged >2 weeks (8 h). The elimination rate of phenytoin was higher for children than adults, and an inverse age relationship was found to exist. Therefore, children might require higher doses than adults for drugs which are metabolized by CYP2C9 to achieve similar therapeutic concentrations. Caution is required if these children are also carrying genetic variants affecting CYP2C9 function. Treluyer et al. reported an association between increased CYP2C9 expression and sudden infant death syndrome. A parallel increase in CYP2C8 and CYP2C9 mediated oxidation of arachidonic acid to epoxyeicosatrienoic acid (EET) and dihydroxyeicosatrienoic acid (HETE) was observed. Although unproven, this increase in EET and HETE may increase the risk of sudden infant death syndrome by decreasing vascular tone.
CYP2C19 and its catalytic activities reach 12%–15% of adult values within 2 months of gestation. At birth, CYP2C19 activity is approximately 30% of adult activity and reaches adults values by 10 years of age., In neonates, the clearance of proton-pump inhibitors (omeprazole and pantoprazole) metabolized by CYP2C19 is reduced, whereas, in children older than 1 year, the clearance is similar to adults., Therefore, children may not require weight-adjusted dose correction for drugs metabolized by CYP2C19 to attain therapeutic concentrations, provided children are not carrying any genetic variants affecting its function.
Cytochrome P450 2D subfamily
CYP2D6 is a major enzyme of this subclass and accounts for <2% of total adult hepatic CYP P450 content. CYP2D6 is essential for the oxidative metabolism of approximately 12% of clinically relevant drugs such as antihypertensive and tricyclic antidepressants. CYP2D6 also catalyzes the O-demethylation of codeine to the active moiety, morphine, and dextromethorphan to dextrorphan that have been used as both in vitro and in vivo CYP2D6 phenotypic probes. Measuring the extent of dextromethorphan O-demethylation is particularly useful in pediatric populations.
The expression of CYP2D6 in fetal liver is debatable. Ladona et al. suggested the absence of CYP2D6 expression in fetal liver. In contrast, Treluyer et al. reported both CYP2D6 protein and mRNA expression at only 5% of adult levels in 30% of the total fetal liver specimens (at <30 weeks of gestational age) examined. Expression was detectable in about 50% of the samples >30 weeks of gestational age, but still at only 15% of adult levels. Interindividual variability in expression of CYP2D6 can be due to the polymorphic nature of this enzyme in adults but may also reflect polymorphisms of regulatory elements controlling developmental expression. CYP2D6 protein expression is increased significantly after birth and reaches 50%–75% of adult values during the neonatal period.
A syndrome of irritability, tachypnea, tremors, jitteriness, increased muscle tone, and temperature instability was observed in infants born to mothers receiving selective serotonin reuptake inhibitors (SSRI). However, it is unclear whether the symptoms result from neonatal withdrawal, from serotoninergic toxicity after in utero exposure or from a combination of both. The delayed in vivo ontogeny of CYP2D6 and CYP3A4 in neonates suggests that the syndrome is because of hyperserotonergic state due to delayed clearance of SSRI (paroxetine) by CYP2D6. The symptoms disappear along time-dependent lines consistent with the maturational patterns of CYP2D6. Caution is required while administering CYP2D6 substrates to children, irrespective of whether they carry functional variants or not.
Cytochrome P450 2E subfamily
CYP2E1 metabolizes short chain dialkyl nitrosamines, organic solvents, and therapeutic drugs including many anesthetics. Many of CYP2E1 substrates induce it. Detectable levels of CYP2E1 protein are found in fetal liver samples as early as in the second trimester. Expression of CYP2E1 mRNA, protein, and enzyme activity rises immediately after birth, and levels increase gradually to approach adult levels by 1 year of age.
CYP2E1s' ability to activate various neurotoxicants, known for their teratogenic activity (e.g., ethanol and toluene) provoked considerable interest in the scientific community to probe the ontogeny of this enzyme in the developing brain. The catalytic activity of CYP2E1 appeared in the human fetal brain within 2 months of gestation. Thus, it would appear that CYP2E1 present in the fetal brain may play a role in the neurotoxicity caused by in utero exposure to neurotoxicants such as ethanol.
Cytochrome P450 3A family
The human CYP3A consists primarily of four enzymes (3A4, 3A5, 3A7, and 3A43) involved in the metabolism of many clinically used drugs, several of which are of potential significance to pediatric practice. These isoforms are located primarily in the liver, small intestine, and kidney.
CYP3A7 is the major CYP isoform in fetal liver. CYP3A4 is absent in fetal liver but increases progressively throughout childhood. It was demonstrated that CYP3A7 enzyme is differentially expressed in the fetus with a transition to CYP3A4/3A5 in the adult. Research on the PK and pharmacodynamics (PD) of cisapride was used to prove the clinical implications of the CYP3A7/3A4 transition. In adult patients, QT prolongation was found to be associated with an excessive dose of cisapride or high plasma levels of the parent drug. Except through a limited access program for specific diseases such as feeding intolerance in neonates, cisapride was banned from the market. Based on the fact that cisapride was metabolized mainly by CYP3A4 and not CYP3A5 or CYP3A7, neonates were assumed to demonstrate deficient metabolic ability. Supporting this hypothesis of the seven microsomal preparations from fetal or neonatal liver aged <7 days, low cisapride metabolism was detectable in four preparations. Kearns et al. further confirmed this hypothesis and showed that terminal elimination rate constant of cisapride increased in patients at 30-week postconception from approximately by tenfold in 52 weeks postconception. The differential substrate specificity of CYP3A4 and CYP3A7 together with a developmental transition demonstrated to have a significant influence on the risk of ADR in neonates, especially those born prematurely. The maturation of CYP3A4 in children is better explained with the use of carbamazepine metabolism. Reports from PK studies and therapeutic drug monitoring (TDM) databases suggest that carbamazepine clearance is higher in children than in adults, thereby necessitating higher doses of the drug on a mg/kg basis to achieve and maintain therapeutic concentrations.
Developmental patterns for the ontogeny of important Phase I DMEs in humans are summarized in [Table 3] (Modified from Leeder and Kearns).
|Table 3: Developmental patterns of important Phase I drug-metabolizing enzymes in humans|
Click here to view
| Ontogeny of Phase II Metabolizing Enzymes|| |
Change in expression of Phase II drug-metabolizing enzymes and their balance during development can considerably alter the PK of a given drug. The Phase II drug-metabolizing enzymes catalyze the reactions which result in pharmacological inactivation or activation or detoxification.
There are three families of GST enzymes: microsomal, cytosolic, and mitochondrial. The cytosolic GST enzyme family consists of six subfamilies: GSTA (alpha), GSTM (mu), GSTO (omega), GSTP (pi), GSTT (theta), and GSTZ (zeta). The enzymes of GST family show overlapping substrate specificities. Hence, it is difficult to characterize the developmental pattern of individual enzyme based on catalytic activity. The advancements in research enabled differentiation between GST enzymes  that allowed to study the GSTM, GSTA, and GSTP ontogeny. GSTP expressed at the highest levels in early gestation (20 weeks), and its expression declined progressively with age to nearly non-detectable levels in adults. GSTA1 and A2 expressed in the fetal lung, but at levels, 0.5%–1% of that observed in the liver. GSTA exhibits higher activity rates in children below 2 years of age and lower activity rates in children above 6 years of age. Older children have high levels of hepatic GTSM activity similar to adults. The levels of GSTM and GSTP in both fetal and postnatal kidney samples were similar to those observed in the liver suggesting uniform expression levels. Although no specific information is available in the literature, administration of electrophilic drugs such as chemotherapeutic agents requires caution in children. Polymorphic variants in GSTs also influence the elimination, increasing the level of complexity to the drug dosing decision process. TDM process is advantageous in such situation to make decisions on dosing to avoid ADRs.
The SULTs are composed of at least 11 distinct isoforms that catalyze sulfate conjugation of a variety of compounds using 3′-phosphoadenosine-5′-phosphosulfate as a donor. Sulfation results in a reduction in the biological activity of endogenous and exogenous compounds. SULTs play a key role in steroid hormone biosynthesis, catecholamine metabolism, and thyroid hormone homeostasis. SULT1A1, SULT1A3, SULT1A6, SULT1B1, SULT1E1, and SULT2A1 are most important for xenobiotic metabolism in humans. SULT1A1 accounts for more than 50% of total SULT protein in the liver. SULT1A1 protein and activities are present in the liver of 10-week-old fetus and do not vary during development. However, fetal SULT1A1 was found to be more sensitive to the inhibitory effects of mefenamic acid and salicylic acid than adult SULT1A1. This suggests that differences between fetal and adult SULT activities could have an influence on drug and hormone metabolism in the fetus. SULT1A3 conjugates circulating catecholamines. Salbutamol and apomorphine are substrates of this enzyme. Expression of SULT1A3 mRNA, protein, and activity (responsible for the metabolism of catecholamines) is high in the liver during early fetal development and decreases substantially in the late fetal development to reach the low levels in adults. High levels of SULT1A3 protect the developing fetus from the adverse effects of circulating catecholamines, whereas the decline in activity during the perinatal period ensures availability of these hormones for the regulation of blood pressure and glucose homeostasis for a successful transition to postnatal life. SULT1E1 has high selectivity and affinity for endogenous estrogens. Endometrium uses sulfation as a specific mechanism of controlling estrogenic stimulation. This enzyme sulfates steroid medication including 17α-ethinylestradiol and is assumed to play a vital role in regulating the biological function of these hormones. SULT1E1 is expressed at higher levels in the fetus, suggesting its role in protecting the developing fetus from the actions of 17-estradiol. SULT2A1 is involved in the biosynthesis of sex steroids and bile acids. SULT2A1 also metabolizes alcohol. SULT2A1 is a second major form of SULT in the liver, but its levels in the extrahepatic tissues are lower compared to other SULTs, which suggests that SULT2A1 substrates do undergo metabolism in the liver. Expression of this enzyme at its higher levels in the liver also suggests that it plays a major role in bile acid homeostasis and protection of the neonate from the toxic effects of bile acids.
The family of UGT catalyzes glucuronidation of hundreds of hydrophobic endogenous molecules (e.g. bilirubin, bile acids, thyroxine, and steroids) and exogenous chemicals including potentially carcinogenic or teratogenic compounds entering the body through diet or air. UGT1, UGT2, UGT3, and UGT8 are members of this family.
The UGT1 and UGT2 gene families are important in the metabolism of many xenobiotics such as morphine, paracetamol, and capable of metabolizing important endogenous compounds (e.g., bilirubin and ethinylestradiol). UGT1A1 is most active towards bilirubin and is absent in the fetal liver. The expression of UGT1A1 is probably triggered by processes associated with birth and mRNA reaches adult levels by 3–6 months of age. UGT1A6 is an important enzyme involved in acetaminophen glucuronidation. It is absent in the fetus, expressed at very low levels in the neonate but reaches adult levels after10 years of age.
Although the precise UGT enzyme responsible for gray baby syndrome remains unknown, it appears to be a member of the UGT2B subfamily. UGT2B7 expression was studied using morphine as a substrate and found to be expressed in fetal liver (15–27 weeks) at 10%–20% of adult levels and its expression increases at birth, reaching adult levels by 2–6 months of age. UGT2B17 is involved in the metabolism of androgenic steroids. In the fetal liver, UGT2B17 is only 3% of adult levels, increasing to 13% in the neonate. No information is available on when the expression reaches to adult levels. Caution is required with implementation of TDM while administering substrates of UGT.
The developmental patterns for the ontogeny of important Phase-II drug-metabolizing enzymes in humans are summarized in [Table 4].
|Table 4: Developmental patterns of important Phase II drug-metabolizing enzymes in humans|
Click here to view
| Impact of Developing Drug-metabolizing Enzymes on Drug–drug Interactions in Children|| |
Drug–drug interactions are well documented in adults, but the studies are often lacking in children due to ethical issues. Hence, we solely depend on case reports. The effect of drug–drug interactions in children alters as DMEs mature. The impact of these interactions is immense in the case of chemotherapy due to the narrow therapeutic window of many chemotherapeutic drugs. For example, cyclosporine (substrate of CYP3A4) is routinely used as an immunosuppressant in solid organ and allogeneic bone marrow transplant patients. When cyclosporine (CYP3A4 substrate) was administered along with voriconazole (CYP3A4 inhibitor), a 2·48-fold rise in the trough concentration of cyclosporine was observed in renal transplant patients aged between 20 and 71 years, and therefore, a reduction in the dose and monitoring of cyclosporine concentration were suggested. However, in children, cyclosporine levels might not rise as expected in adults due to the possible increased activity of CYP3A4 compared to adults. Hence, reducing the dose of cyclosporine when given along with voriconazole in children might compromise its efficacy. Thus, the impact of the developmental pattern of enzymes has to be taken into account while assessing consequences of drug–drug interactions in children.
| Role of Therapeutic Drug Monitoring in Optimizing Therapy|| |
As the DMEs are still in the process of development in children, it becomes necessary to monitor the drug levels with respect to their effects. As an example, TDM is in use for monitoring busulfan levels during administration of the conditioning regimen in children receiving hematopoietic stem cell transplantation. The adverse effects of busulfan include interstitial pulmonary fibrosis, hyperpigmentation, hepatic sinusoidal obstruction syndrome, and seizures. Busulfan undergoes glutathione conjugation by GST, which is liable for variability with the age of the children. Similarly, younger children receiving ifosfamide, an anticancer drug, might be at higher risk of developing nephrotoxicity throughincreased production of chloroacetaldehyde by CYP3A enzyme (a nephrotoxic metabolite of ifosfamide). TDM can help in such case to monitor the levels of parent drug and metabolite to control dosing. TDM may be especially useful in monitoring pharmacological effects of immunosuppressant drugs in children. However, for drugs such as voriconazole, patients <12-year-old required higher dosages to maintain drug levels within the targeted therapeutic range than older patients. Similarly, there is a need for TDM in children receiving antiretroviral therapy. Application of TDM in individualizing therapy for epilepsy among children could be especially useful in minimizing ADRs. In this direction, the German-Swiss-Austrian competence network for TDM in child and adolescent psychiatry has been initiated to collect and collate demographic, safety, and efficacy data along with blood concentrations of psychotropic drugs in children and adolescents.
| Future Perspectives|| |
Understanding the developmental patterns of DMEs helps in the development of more appropriate PK models for pediatric drug development. As these age-associated differences are enzyme specific, all studies in developmental pharmacology should use specific validated phenotypic markers along with pharmacogenetic markers. Further, it is validated that pediatric PK is not just an extrapolation of adult PK indicating that no single method could predict dosing in children. Thus, more studies including both in vitro and clinical studies are essential for establishing PK models for important drugs used in children.In vitro characterization of metabolic enzymes is pivotal. As drugs are substrates for many enzymes, clinically significant role of these age-associated changes in the enzyme activity can be obtained only by clinical PK investigations. Thus, both in vitro and in vivo understanding of developmental patterns of the enzymes are mandated in future studies. Sophisticated software (SimCYP ®, NONMEM, PK-Sim ®, and MoBi ®) have enabled us to apply population and physiology-based PK modeling based on ontogeny functions to develop appropriate pediatric dosing guidelines.
Recently, another dimension has been added to the existing complexity, with the accumulated data on the role of gut microbiota on drug metabolism. Gut microbiota plays a role in the metabolism of important drugs. Thus, microbiota can influence drug metabolism through diet, environment, and route of administration. Recent evidence attributed pediatric gut microbiome to various diseases from diabetes to asthma. Thus, emphasis on investigating the role of gut microbiome on PK and PD of drugs in children warranted in the near future.
| Conclusion|| |
Expression of many DMEs alters during the developmental phases in children that markedly affect drug response. Although overlooking these changes has led to several therapeutic misadventures with consequent adverse effects, we hope that a greater awareness and the application of tools such as physiologically based PK modeling will prevent such complications in the future. Further, as we gain more knowledge regarding the mechanisms regulating DME ontogeny, we will be able to understand better and predict an individual's metabolic capacity and drug response which permit adjustment of therapies accordingly.
Financial support and sponsorship
Chakradhara Rao S Uppugunduri received support partly from CANSEARCH Foundation and supported by salary from Swiss National Science Foundation (Grant number: 153389).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Weiss CF, Glazko AJ, Weston JK. Chloramphenicol in the newborn infant. A physiologic explanation of its toxicity when given in excessive doses. N Engl J Med 1960;262:787-94.
Alam SN, Roberts RJ, Fischer LJ. Age-related differences in salicylamide and acetaminophen conjugation in man. J Pediatr 1977;90:130-5.
Anderson GD, Lynn AM. Optimizing pediatric dosing: A developmental pharmacologic approach. Pharmacotherapy 2009;29:680-90.
Impicciatore P, Choonara I, Clarkson A, Provasi D, Pandolfini C, Bonati M. Incidence of adverse drug reactions in paediatric in/out-patients: A systematic review and meta-analysis of prospective studies. Br J Clin Pharmacol 2001;52:77-83.
O'Hara K, Wright IM, Schneider JJ, Jones AL, Martin JH. Pharmacokinetics in neonatal prescribing: Evidence base, paradigms and the future. Br J Clin Pharmacol 2015;80:1281-8.
Hoppu K, Anabwani G, Garcia-Bournissen F, Gazarian M, Kearns GL, Nakamura H, et al.
The status of paediatric medicines initiatives around the world – What has happened and what has not? Eur J Clin Pharmacol 2012;68:1-10.
Food and Drug Administration, HHS. International Conference on Harmonisation; Guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice. Fed Regist 2000;65:78493-4.
Hines RN. Developmental expression of drug metabolizing enzymes: Impact on disposition in neonates and young children. Int J Pharm 2013;452:3-7.
Roberts-Thomson SJ, McManus ME, Tukey RH, Gonzalez FF, Holder GM. The catalytic activity of four expressed human cytochrome P450s towards benzo[a]pyrene and the isomers of its proximate carcinogen. Biochem Biophys Res Commun 1993;192:1373-9.
McLemore TL, Adelberg S, Liu MC, McMahon NA, Yu SJ, Hubbard WC, et al.
Expression of CYP1A1 gene in patients with lung cancer: Evidence for cigarette smoke-induced gene expression in normal lung tissue and for altered gene regulation in primary pulmonary carcinomas. J Natl Cancer Inst 1990;82:1333-9.
Edwards RJ, Adams DA, Watts PS, Davies DS, Boobis AR. Development of a comprehensive panel of antibodies against the major xenobiotic metabolising forms of cytochrome P450 in humans. Biochem Pharmacol 1998;56:377-87.
Sonnier M, Cresteil T. Delayed ontogenesis of CYP1A2 in the human liver. Eur J Biochem 1998;251:893-8.
Kraus DM, Fischer JH, Reitz SJ, Kecskes SA, Yeh TF, McCulloch KM, et al.
Alterations in theophylline metabolism during the first year of life. Clin Pharmacol Ther 1993;54:351-9.
Le Guennec JC, Billon B. Delay in caffeine elimination in breast-fed infants. Pediatrics 1987;79:264-8.
Shimada T, Yamazaki H, Mimura M, Wakamiya N, Ueng YF, Guengerich FP, et al.
Characterization of microsomal cytochrome P450 enzymes involved in the oxidation of xenobiotic chemicals in human fetal liver and adult lungs. Drug Metab Dispos 1996;24:515-22.
Gu J, Su T, Chen Y, Zhang QY, Ding X. Expression of biotransformation enzymes in human fetal olfactory mucosa: Potential roles in developmental toxicity. Toxicol Appl Pharmacol 2000;165:158-62.
Su T, Sheng JJ, Lipinskas TW, Ding X. Expression of CYP2A genes in rodent and human nasal mucosa. Drug Metab Dispos 1996;24:884-90.
Litalien C, Théorêt Y, Faure C. Pharmacokinetics of proton pump inhibitors in children. Clin Pharmacokinet 2005;44:441-66.
Koukouritaki SB, Manro JR, Marsh SA, Stevens JC, Rettie AE, McCarver DG, et al.
Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther 2004;308:965-74.
Loughnan PM, Greenwald A, Purton WW, Aranda JV, Watters G, Neims AH. Pharmacokinetic observations of phenytoin disposition in the newborn and young infant. Arch Dis Child 1977;52:302-9.
Suzuki Y, Mimaki T, Cox S, Koepke J, Hayes J, Walson PD. Phenytoin age-dose-concentration relationship in children. Ther Drug Monit 1994;16:145-50.
Tréluyer JM, Benech H, Colin I, Pruvost A, Chéron G, Cresteil T. Ontogenesis of CYP2C-dependent arachidonic acid metabolism in the human liver: Relationship with sudden infant death syndrome. Pediatr Res 2000;47:677-83.
Strolin Benedetti M, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol 2005;1:447-71.
Marier JF, Dubuc MC, Drouin E, Alvarez F, Ducharme MP, Brazier JL. Pharmacokinetics of omeprazole in healthy adults and in children with gastroesophageal reflux disease. Ther Drug Monit 2004;26:3-8.
Tran A, Rey E, Pons G, Pariente-Khayat A, D'Athis P, Sallerin V, et al.
Pharmacokinetic-pharmacodynamic study of oral lansoprazole in children. Clin Pharmacol Ther 2002;71:359-67.
Ladona MG, Lindström B, Thyr C, Dun-Ren P, Rane A. Differential foetal development of the O- and N-demethylation of codeine and dextromethorphan in man. Br J Clin Pharmacol 1991;32:295-302.
Treluyer JM, Jacqz-Aigrain E, Alvarez F, Cresteil T. Expression of CYP2D6 in developing human liver. Eur J Biochem 1991;202:583-8.
Johnsrud EK, Koukouritaki SB, Divakaran K, Brunengraber LL, Hines RN, McCarver DG. Human hepatic CYP2E1 expression during development. J Pharmacol Exp Ther 2003;307:402-7.
Schuetz JD, Beach DL, Guzelian PS. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics 1994;4:11-20.
Kearns GL, Robinson PK, Wilson JT, Wilson-Costello D, Knight GR, Ward RM, et al.
Cisapride disposition in neonates and infants: In vivo
reflection of cytochrome P450 3A4 ontogeny. Clin Pharmacol Ther 2003;74:312-25.
Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ, et al.
Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation. Biochem Pharmacol 1994;47:1969-79.
Leeder JS, Kearns GL. Pharmacogenetics in pediatrics. Implications for practice. Pediatr Clin North Am 1997;44:55-77.
Strange RC, Davis BA, Faulder CG, Cotton W, Bain AD, Hopkinson DA, et al.
The human glutathione S-transferases: Developmental aspects of the GST1, GST2, and GST3 loci. Biochem Genet 1985;23:1011-28.
Beckett GJ, Howie AF, Hume R, Matharoo B, Hiley C, Jones P, et al.
Human glutathione S-transferases: Radioimmunoassay studies on the expression of alpha-, mu- and pi-class isoenzymes in developing lung and kidney. Biochim Biophys Acta 1990;1036:176-82.
Stanley EL, Hume R, Coughtrie MW. Expression profiling of human fetal cytosolic sulfotransferases involved in steroid and thyroid hormone metabolism and in detoxification. Mol Cell Endocrinol 2005;240:32-42.
Vietri M, Pietrabissa A, Mosca F, Rane A, Pacific GM. Human adult and foetal liver sulphotransferases: Inhibition by mefenamic acid and salicylic acid. Xenobiotica 2001;31:153-61.
Duanmu Z, Weckle A, Koukouritaki SB, Hines RN, Falany JL, Falany CN, et al.
Developmental expression of aryl, estrogen, and hydroxysteroid sulfotransferases in pre- and postnatal human liver. J Pharmacol Exp Ther 2006;316:1310-7.
Kitada H, Miyata M, Nakamura T, Tozawa A, Honma W, Shimada M, et al.
Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity. J Biol Chem 2003;278:17838-44.
Strassburg CP, Strassburg A, Kneip S, Barut A, Tukey RH, Rodeck B, et al.
Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut 2002;50:259-65.
Pacifici GM, Säwe J, Kager L, Rane A. Morphine glucuronidation in human fetal and adult liver. Eur J Clin Pharmacol 1982;22:553-8.
Romero AJ, Le Pogamp P, Nilsson LG, Wood N. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther 2002;71:226-34.
Chen YT, Trzoss L, Yang D, Yan B. Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: Postnatal surge and organ-dependent regulation. Toxicology 2015;330:55-61.
del Mar Fernández De Gatta M, Santos-Buelga D, Domínguez-Gil A, García MJ. Immunosuppressive therapy for paediatric transplant patients: Pharmacokinetic considerations. Clin Pharmacokinet 2002;41:115-35.
Kang HM, Lee HJ, Cho EY, Yu KS, Lee H, Lee JW, et al.
The clinical significance of voriconazole therapeutic drug monitoring in children with invasive fungal infections. Pediatr Hematol Oncol 2015;32:557-67.
Burger DM. The role of therapeutic drug monitoring in pediatric HIV/AIDS. Ther Drug Monit 2010;32:269-72.
Walson PD. Role of therapeutic drug monitoring (TDM) in pediatric anti-convulsant drug dosing. Brain Dev 1994;16:23-6.
Egberts KM, Mehler-Wex C, Gerlach M. Therapeutic drug monitoring in child and adolescent psychiatry. Pharmacopsychiatry 2011;44:249-53.
Mahmood I. Prediction of drug clearance in children from adults: A comparison of several allometric methods. Br J Clin Pharmacol 2006;61:545-57.
Jourova L, Anzenbacher P, Anzenbacherova E. Human gut microbiota plays a role in the metabolism of drugs. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016;160:317-26.
Arora SK, Dewan P, Gupta P. Microbiome: Paediatricians' perspective. Indian J Med Res 2015;142:515-24.
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[Table 1], [Table 2], [Table 3], [Table 4]