Drug Biotransformation The majority of drug biotransformation occurs in the liver Extrahepatic tissues do contain drug-metabolizing enzymes, although their relative contributions to overall biotransformation are typically not as pronounced as those of the liver Drug biotransformation reactions are categorized into phase I (e.g., CYPmediated oxidation) and phase II (e.g., UGT-mediated glucuronidation) The relative contribution of CYP enzymes to drug metabolism is summarized in Fig 79.3 The ontogeny of drug metabolism enzymes, summarized by Hines,1 is characterized to a larger extent compared with drug transporters and is essential in determining the potential genotype-phenotype relationship for the individual child FIG 79.3 Relative contribution of cytochrome Ps (CYPs) to drug metabolism The estimated contributions of individual human CYPs to the metabolism of clinical drugs (Modified from Zanger UM, Schwab M Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation Pharmacol Ther 2013;138[1]:103–141.) CYP2D6 CYP2D6 is an important phase 1 drug metabolizing enzyme (DME) that contributes to the metabolism of approximately 20% to 25% of drugs used clinically,9,10 despite comprising only 2% to 5% of the total hepatic CYP content.11,12 Expression is undetectable in the fetus but rapidly increases postnatally to near adult levels within the first few weeks.1 CYP2D6 is the predominant pathway for bioactivation or elimination of many cardiovascular medications, including antiarrhythmics and β-blockers.13 The highly polymorphic CYP2D6 gene resides on chromosome 22q13.1, located close to two nonfunctional genes, CYP2D7 and CYP2D8.14,15 Currently over 100 allelic variants have been identified (http://www.cypalleles.ki.se/cyp2d6.htm), with an extensive range of absent, decreased, normal, or excessive allelic functions resulting in variable interindividual CYP2D6 enzyme activity.16 Given the array of possible allelic functionality, it is not surprising that hepatic CYP2D6 protein expression varies dramatically among individuals.17 Additionally, this expression can be highly variable within the world's population and various ethnic groups.18 The poor metabolizer phenotype, comprising individuals carrying no functional alleles (i.e., *3, *4, *5, *6), and the ultrarapid metabolizer phenotype, compromising individuals carrying an increase of functional alleles with a normally functional allele, represent the broad range of possible enzyme activity A higher risk of adverse events or treatment failure can occur in these phenotypic groups based on the drug involved For instance, most antiarrhythmic drugs are metabolically deactivated by CYP2D6, thus placing poor metabolizers at higher risk for drug accumulation, leading to adverse events or toxicity Conversely, in the same example, ultrarapid metabolizer phenotypes would be at risk for extensive metabolism and clearance of the active drug, potentially leading to decreased efficacy This example is contrasted with codeine, where CYP2D6 metabolically activates the drug to produce morphine In this scenario, the poor metabolizer phenotype is susceptible to treatment failure or decreased efficacy secondary to decreased morphine production Conversely, the ultrarapid metabolizer phenotype is at risk for opioid toxicity due to increased plasma concentration of morphine from enhanced CYP2D6-mediated production CYP2C9 CYP2C9, comprising an average of 20% of the total hepatic CYP content,12 contributes to the metabolism of approximately 12% to 13% of clinically used drugs.19–21 Expression of CYP2C9 is minimal during early fetal life, increasing to levels 10% of adult values in the third trimester.1 After birth to 5 months of age, protein expression of CYP2C9 is about 25% of adult levels.22 Of concern, this age group displayed the highest degree of interindividual variability of CYP2C9 expression, with 50% of the infants having no change in expression compared with third-trimester fetal livers; conversely, others demonstrate expression nearly equivalent to adult levels Collectively, this translates to a nearly 35-fold range in enzyme expression over the first 5 months of life Less variability is observed from 5 months to 18 years, where CYP2C9 levels were approximately 50% of adult values However, an absence of adult levels observed in some postpubertal samples by Treluyer et al suggests that the maturation of CYP2C9 could occur later in childhood.23 This determination of late CYP2C9 is not consistent with in vivo pharmacokinetic data in children, where metabolism of CYP2C9 substrates was comparable to adults.1 Clearly these discrepancies warrant further investigation, but they likely result from pharmacogenetic and physiologic changes in liver mass, as summarized further on with warfarin metabolism.24 Most of the expression and metabolic activity of CYP2C9 occurs in the liver; however, CYP2C9 is quantitatively the second most common isoform (~15%) found in the human intestine following the CYP3A subfamily (~80%).25 Despite the human intestinal content being of an order of magnitude less than that of the liver,12 the large degree of variability of intestinal CYP2C9 content and activity among individuals could result in variable drug exposure secondary to decreased presystemic clearance of CYP2C9 substrates (e.g., fluvastatin, warfarin) Collectively, there is a paucity of data regarding the role of intestinal CYPs and their respective contributions to drug exposure, and nothing related to the ontogeny of CYP2C9 in extrahepatic tissue is known For the purpose of precision therapeutics, the role of extrahepatic CYP2C9 and CYP3A should be considered in the design of pharmacogenetic and pharamacogenomic trials and clinical decision making CYP2C9, located on chromosome 10q23.33, exhibits genetic polymorphism with over 60 allelic variants currently reported (http://www.cypalleles.ki.se/cyp2c9.htm) As opposed to CYP2D6, most CYP2C9 allelic variants result only in a decrease of function In fact, CYP2C9*2