and *3, the most investigated CYP2C9 alleles, result in decreased activity, although the degree of change is substrate-specific Comparatively, the CYP2C9*3 allele results in a greater decrease in enzymatic activity (~70% to 90%).19 The most common application of CYP2C9 polymorphism is related to warfarin pharmacogenetics, where it accounts for ~15% to 20% of the variation in dose requirements.26 Further details of warfarin pharmacogenomics are detailed further on, under Practical Applications CYP2C19 Despite comprising only 1% to 4% of the total hepatic CYP content,19 CYP2C19 is the second most important DME in the CYP2C subfamily, estimated to contribute to ~7% metabolism of all clinically used drugs.20 It is almost exclusively expressed in the liver and comprises only 2% of CYP expression at the intestinal tract.25 Expression of CYP2C19 occurs in the fetus (~10% to 20% of adult levels), and it undergoes considerable change during gestation or immediately postpartum.22 In contrast to CYP2C9, from birth to 5 months of age there was an increasing trend of CYP2C19 expression, approaching 50% to 75% of adult levels There is variability in this within this age group, but less compared with CYP2C9 Conversely, from infancy (>5 months) through puberty, a 21-fold range of enzyme expression was observed by Koukouritaki et al.22 Postpubertal expression was equivalent to adult levels, which is in contrast to the aforementioned findings by Treluyer et al.23 for CYP2C9 CYP2C19, also located on chromosome 10q23.33, is highly polymorphic, having over 35 reported allelic variants (http://www.cypalleles.ki.se/2cyp2c19.htm) Two allelic variants, CYP2C19*2 and *3 result in no functional activity, and CYP2C19*17 produces increased enzymatic activity.27 The variant allelic frequency of CYP2C19*2 fluctuates within different population groups, being nearly 15% in whites and blacks and 30% in Asians.27 Similar to CYP2D6, CYP2C19 is categorized into phenotype groups: ultrarapid, extensive, intermediate, and poor metabolizers The ultrarapid metabolizers, accounting for between 5% and 30% of patients, carry two increased-activity alleles (e.g., *17/*17) or one functional allele with one increased-activity allele (e.g., *1/*17) Extensive metabolizers, accounting between 35% and 50% of patients, carry two functional alleles (e.g., *1/*1) Intermediate metabolizers, accounting for 18% and 45% of patients, carry one functional plus one decreased-function allele (e.g., *1/*2, *1/*3) Poor metabolizers, accounting for the 2% to 15% of patients, carry two decreasedfunction alleles (e.g., *2/*2, *2/*3, *3/*3) Interpretation of the potential risk for adverse events and evaluation of the efficacy profiles must be performed in the context of the substrate involved, comparable to the descriptions provided previously for CYP2D6 For instance, proton pump inhibitors (e.g., omeprazole, pantoprazole) are substrates for CYP2C19, resulting in deactivation of the compound Therefore a poor metabolizer of CYP2C19 would have increased AUC (e.g., systemic exposure) of the drug and thus an increased risk of adverse events Conversely, CYP2C19 is responsible for the activation of the antithrombotic agent clopidogrel Thus poor metabolizers of CYP2C19 would have decreased AUC and an increased risk of treatment failure Clopidogrel is discussed in further detail under Practical Applications CYP3A4/5/7 CYP3A is qualitatively and quantitatively the most important subfamily of CYP enzymes, comprising an average of 30% to 35% of the total hepatic CYP content12,19 and contributing to the metabolism of 30% to 45% of all drugs.19,28 The CYP3A subfamily is composed of four CYP enzymes (3A4, 3A5, 3A7, 3A43) CYP3A43 is minimally expressed and does not participate in drug metabolism CYP3A7 is the dominant CYP3A enzyme expressed in fetal life, declining steadily over the first year.1 Conversely, CYP3A4 is minimally expressed in fetal life (~10% to 20% of adult levels), increases to 30% to 60% of adult levels after 1 week of age, and approaches the adult level at 1 year.1 CYP3A5 expression is highly variable, does not have an age-dependent expression pattern, and is more highly expressed in black than in white and Hispanic populations.29 In adults, increased clearance of CYP3A4 substrates occurs in females compared with males.30 However, there is a paucity of data related to the influence of gender on CYP3A4-mediated clearance in children As mentioned earlier, in the CYP2C9 category, CYP3A comprises ~80% of the total CYP content in the enterocyte25 and should be considered in the evaluation of presystemic clearance of CYP3A substrates Of note, the total CYP content in the liver and intestinal tract can be significantly increased in blacks secondary to a higher allelic frequency of the functional CYP3A5 *1, which increases CYP3A5 content relative to nonexpressers.31 CYP3A, located on chromosome 7q22.1, has an 85% similar sequence identity among the three major enzymes (CYP3A4, CYP3A5, CYP3A7), making substrate specificity and the impact of individual isozyme polymorphism difficult to interpret Currently over 40 allelic variants are reported (http://www.cypalleles.ki.se), yet they are less well described compared with CYP2D6 The CYP3A4*22 allele, intron 6 C>T variant, is associated with decreased CYP3A4 expression both in vitro and in vivo.32,33 In fact, carriers of the variant T allele taking a statin metabolized by a CYP3A4-mediated pathway (e.g., atorvastatin, lovastatin, simvastatin) require significantly lower statin dosing compared with those carrying the reference genotype (CC)32 secondary to decrease clearance of the parent drug and active metabolite.33 Additionally, in the study by Klein et al., variation in the peroxisome proliferator activated receptor alpha (PPARα) influenced CYP3A4 phenotype and accounted for 10% of the variability in atorvastatin hydroxylase activity CYP3A5*3, the most common CYP3A5 allelic variant, leads to decrease enzyme expression while the presence of a CYP3A5*1 gain-of-function mutation, leading to an increase in liver and intestinal tract CYP3A5 content.31 The latter genotype is found in ~60% of blacks and ~30% of whites.31 Udp-Glucuronosyl Transferases UGTs are most important phase 2 metabolizing superfamily of enzymes responsible for the conjugation of xenobiotics, developing a more polar compound for elimination UGTs account for ~35% of phase 2 enzymatic metabolism of all drugs.20 UGTs are subdivided into two gene families, UGT1 (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10) located on chromosome 2q37 and UGT2 (2A1, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17) located on chromosome 4q13-13.2 The ontogenic profiles of the UGTs are less characterized compared with CYPs UGT1A1 is absent in the fetus, increasing immediately after birth and approaching adult levels at 3 to 6 months.34 UGT1A6 is present at low levels (1% to 10%) during fetal life, slowly increases after birth, and approaches 50% of adult levels after birth In contrast to UGT1A1, complete maturation of UGT1A6 occurs near puberty.34 UGT2B7 is detectable in the fetus (~10% to 20% of adult levels), with adult levels achieved at 2 to 3 months of age.34 Hundreds of UGT polymorphisms are reported (www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles/); however, the importance of these genetic variants requires further elucidation