Implications of Pharmacogenomics to the Management of IBS

The objectives are to review the role of pharmacogenomics in drug metabolism of medications typically used in patients with irritable bowel syndrome (IBS) focusing predominantly on cytochrome P450 metabolism. Other aims are to provide examples of genetic variation of receptors or intermediary pathways that are targets for IBS drugs and to critically appraise the situations where precision medicine is impacting health in IBS. Pharmacogenomics impacts both pharmacokinetics and pharmacodynamics. Although large clinical trials have not incorporated testing for genetic variations that could impact the efficacy of medications in IBS, there are therapeutic advantages to inclusion of pharmacogenomics testing for individual patients, as has been demonstrated particularly in the treatment with central neuromodulators in psychiatry practice. Clinical practice in IBS is moving in the same direction with the aid of commercially available tests focused on drug metabolism. Specific mechanisms leading to pathophysiology of IBS are still poorly characterized, relative to diseases such as cancer and inflammatory bowel disease, and, therefore, pharmacogenomics related to drug pharmacodynamics is still in its infancy and requires extensive future research. With increased attention to pharmacogenomics affecting drug metabolism, it is anticipated that pharmacogenomics will impact care of IBS. The objectives are to review the role of pharmacogenomics in drug metabolism of medications typically used in patients with irritable bowel syndrome (IBS) focusing predominantly on cytochrome P450 metabolism. Other aims are to provide examples of genetic variation of receptors or intermediary pathways that are targets for IBS drugs and to critically appraise the situations where precision medicine is impacting health in IBS. Pharmacogenomics impacts both pharmacokinetics and pharmacodynamics. Although large clinical trials have not incorporated testing for genetic variations that could impact the efficacy of medications in IBS, there are therapeutic advantages to inclusion of pharmacogenomics testing for individual patients, as has been demonstrated particularly in the treatment with central neuromodulators in psychiatry practice. Clinical practice in IBS is moving in the same direction with the aid of commercially available tests focused on drug metabolism. Specific mechanisms leading to pathophysiology of IBS are still poorly characterized, relative to diseases such as cancer and inflammatory bowel disease, and, therefore, pharmacogenomics related to drug pharmacodynamics is still in its infancy and requires extensive future research. With increased attention to pharmacogenomics affecting drug metabolism, it is anticipated that pharmacogenomics will impact care of IBS. What You Need to KnowBackgroundPharmacogenomics is the study of genetic variation and its effects on therapeutic effects of pharmacological agents. This article assesses the influence of pharmacogenomics on pharmacokinetics and pharmacodynamics in irritable bowel syndrome (IBS).FindingsPharmacogenomics in IBS is in its infancy. The most significant impact to date in IBS is effect of genetic variation on pharmacokinetics of drug metabolism (eg, central modulators or analgesics).Implications for patient careWith increased attention to and ease of testing of pharmacogenomics of drug metabolism, this discipline will impact the selection of agents and doses in IBS (especially central neuromodulators). Pharmacogenomics is the study of genetic variation and its effects on therapeutic effects of pharmacological agents. This article assesses the influence of pharmacogenomics on pharmacokinetics and pharmacodynamics in irritable bowel syndrome (IBS). Pharmacogenomics in IBS is in its infancy. The most significant impact to date in IBS is effect of genetic variation on pharmacokinetics of drug metabolism (eg, central modulators or analgesics). With increased attention to and ease of testing of pharmacogenomics of drug metabolism, this discipline will impact the selection of agents and doses in IBS (especially central neuromodulators). Pharmacogenomics is the discipline that combines the study of genetic variation and its effects on therapeutic effects of pharmacological agents. This discipline focuses on the identification of genetic variants that influence drug effects, typically through alterations in pharmacokinetics or pharmacodynamics. Pharmacokinetics refers to how the drug is absorbed, distributed, metabolized, or eliminated. Pharmacodynamics refers to modification in the drug’s target or perturbation of the biological pathways that shape a patient's sensitivity to a drug’s pharmacological effects.1Relling M.V. Evans W.E. Pharmacogenomics in the clinic.Nature. 2015; 526: 343-350Crossref PubMed Scopus (493) Google Scholar A typical example in the context of irritable bowel syndrome (IBS) is the variation in the potential effectiveness of central neuromodulators or the development of adverse effects impacting compliance with the drug. The objectives of this article are to assess the influence of pharmacogenomics on pharmacokinetics (with specific focus on metabolism) and pharmacodynamics as it applies to IBS and to assess the evidence to date about the impact of precision medicine in the context of IBS. A glossary of terms is included in Box 1.Box 1Glossary of TermsGenome is the entire set of genetic instructions found in a cell. In humans, the genome consists of 23 pairs of chromosomes, found in the nucleus, as well as a small chromosome found in the cells' mitochondria. Each set of 23 chromosomes contains approximately 3.1 billion bases of DNA sequence.Somatic DNA: A somatic cell refers to any cell in the body except sperm and egg cells; somatic cells are diploid, having 2 sets of chromosomes, 1 inherited from each parent; the DNA in those chromosomes is called somatic DNA. Mutations in the somatic DNA may result in disease, typically in cancers. However, such somatic mutations are not passed on to the offspring.Germline DNA is the DNA in germ line cells, that is, eggs and sperm that are used by sexually-reproducing organisms to pass on genes from generation to generation.DNA variation is a general term to indicate diversity of genomes in a species.DNA variants: There are 2 main types of DNA variants: polymorphisms and histone variants.A polymorphism involves 1 of 2 or more variants of a particular DNA sequence. The most common type of polymorphism involves variation at a single base pair, such as a change from threonine (T) to cytosine (C). Such a variation is called a single nucleotide polymorphism, which occurs in at least 1% of the population and may correlate with disease, drug response, and other phenotypes. Polymorphisms can also be much larger in size and involve long stretches of DNA which may be present (inserted) or absent (deleted). Deletions and insertions tend to be especially harmful when the number of missing or extra base pairs is not a multiple of 3.A histone is a protein that provides structural support to a chromosome. Given the length of DNA molecules, they are able to wrap around complexes of histone proteins, giving the chromosome a more compact shape that can fit in the cell nucleus. Some variants of histones are associated with the regulation of gene expression.DNA sequencing identifies an individual’s variants by comparing the DNA sequence of an individual to the DNA sequence of a reference genome maintained by the Genome Reference Consortium. In addition to single nucleotide polymorphisms, insertions and deletions mentioned above, there may be substitutions when multiple nucleotides are altered from the reference sequence, or structural variants, where large sections of a chromosome or even whole chromosomes are duplicated, deleted, or rearranged in some manner.Characterization of DNA sequence variants (guideline from American College of Medical Genetics and Genomics):Pathogenic: A sequence variant that is previously reported and is a recognized cause of the disorder.Likely pathogenic: A sequence variant that is previously unreported and is of the type which is expected to cause the disorder.Variant of unknown significance: A sequence variant that is previously unreported and is of the type which may or may not be causative of the disorder.Likely benign: A sequence variant that is previously unreported and is probably not causative of disease.Benign: A sequence variant that is previously reported and is a recognized neutral variant.Sequence variant: A variant that is previously not known or expected to be causative of disease, but is found to exist in people with a particular disease or disorder.As a result of mutations, a gene can differ among individuals in terms of its DNA sequence. The differing sequences are referred to as alleles. A gene's location on a chromosome is termed a locus (from the Latin word for place). If a person has the same allele on both members of a chromosome pair, that person is a homozygote. If the alleles differ in DNA sequence, that person is a heterozygote. The combination of alleles that is present at a given locus is termed the genotype.All genetic variation originates from the process known as mutation, which is defined as a change in DNA sequence. Mutations can affect either germline cells or somatic cells.One type of single-gene mutation is the base-pair substitution, in which one base pair is replaced by another. This can result in a change in the amino acid sequence. However, because of the redundancy of the genetic code, many of these mutations do not change the amino acid sequence (silent substitutions) and, therefore, they usually have no effect.Base-pair substitutions that alter amino acids may be 1 of 2 basic types: missense mutations, which produce a change in a single amino acid, and nonsense mutations, which produce 1 of the 3 stop codons (UAA, UAG, or UGA) in the messenger RNA (mRNA), thereby terminating translation of the mRNA (shorter polypeptide chain). Conversely, if a stop codon is altered so that it encodes an amino acid, an abnormally elongated polypeptide can be produced. These alterations of amino acid sequences can have profound consequences.Because codons consist of groups of 3 base pairs, insertions or deletions can alter the downstream codons, resulting in a frameshift mutation.Other types of mutation can alter the regulation of transcription or translation. A promoter mutation can decrease the affinity of RNA polymerase for a promoter site, often resulting in reduced production of mRNA and, thus, decreased production of a protein.Mutations can also interfere with the splicing of introns, as mature mRNA is formed from the primary mRNA transcript. Splice-site mutations, those that occur at intron–exon boundaries, alter the splicing signal that is necessary for proper excision of an intron.Further Readinga.National Human Genome Research Institute; https://www.genome.govb.Lynn B, Jorde LB, Carey JC, Bamshad MJ. Genetic variation: Its origin and detection. IN: Medical genetics, 5th ed. New York, Elsevier, 2016:28–59. Genome is the entire set of genetic instructions found in a cell. In humans, the genome consists of 23 pairs of chromosomes, found in the nucleus, as well as a small chromosome found in the cells' mitochondria. Each set of 23 chromosomes contains approximately 3.1 billion bases of DNA sequence. Somatic DNA: A somatic cell refers to any cell in the body except sperm and egg cells; somatic cells are diploid, having 2 sets of chromosomes, 1 inherited from each parent; the DNA in those chromosomes is called somatic DNA. Mutations in the somatic DNA may result in disease, typically in cancers. However, such somatic mutations are not passed on to the offspring. Germline DNA is the DNA in germ line cells, that is, eggs and sperm that are used by sexually-reproducing organisms to pass on genes from generation to generation. DNA variation is a general term to indicate diversity of genomes in a species. DNA variants: There are 2 main types of DNA variants: polymorphisms and histone variants. A polymorphism involves 1 of 2 or more variants of a particular DNA sequence. The most common type of polymorphism involves variation at a single base pair, such as a change from threonine (T) to cytosine (C). Such a variation is called a single nucleotide polymorphism, which occurs in at least 1% of the population and may correlate with disease, drug response, and other phenotypes. Polymorphisms can also be much larger in size and involve long stretches of DNA which may be present (inserted) or absent (deleted). Deletions and insertions tend to be especially harmful when the number of missing or extra base pairs is not a multiple of 3. A histone is a protein that provides structural support to a chromosome. Given the length of DNA molecules, they are able to wrap around complexes of histone proteins, giving the chromosome a more compact shape that can fit in the cell nucleus. Some variants of histones are associated with the regulation of gene expression. DNA sequencing identifies an individual’s variants by comparing the DNA sequence of an individual to the DNA sequence of a reference genome maintained by the Genome Reference Consortium. In addition to single nucleotide polymorphisms, insertions and deletions mentioned above, there may be substitutions when multiple nucleotides are altered from the reference sequence, or structural variants, where large sections of a chromosome or even whole chromosomes are duplicated, deleted, or rearranged in some manner. Characterization of DNA sequence variants (guideline from American College of Medical Genetics and Genomics): Pathogenic: A sequence variant that is previously reported and is a recognized cause of the disorder. Likely pathogenic: A sequence variant that is previously unreported and is of the type which is expected to cause the disorder. Variant of unknown significance: A sequence variant that is previously unreported and is of the type which may or may not be causative of the disorder. Likely benign: A sequence variant that is previously unreported and is probably not causative of disease. Benign: A sequence variant that is previously reported and is a recognized neutral variant. Sequence variant: A variant that is previously not known or expected to be causative of disease, but is found to exist in people with a particular disease or disorder. As a result of mutations, a gene can differ among individuals in terms of its DNA sequence. The differing sequences are referred to as alleles. A gene's location on a chromosome is termed a locus (from the Latin word for place). If a person has the same allele on both members of a chromosome pair, that person is a homozygote. If the alleles differ in DNA sequence, that person is a heterozygote. The combination of alleles that is present at a given locus is termed the genotype. All genetic variation originates from the process known as mutation, which is defined as a change in DNA sequence. Mutations can affect either germline cells or somatic cells. One type of single-gene mutation is the base-pair substitution, in which one base pair is replaced by another. This can result in a change in the amino acid sequence. However, because of the redundancy of the genetic code, many of these mutations do not change the amino acid sequence (silent substitutions) and, therefore, they usually have no effect. Base-pair substitutions that alter amino acids may be 1 of 2 basic types: missense mutations, which produce a change in a single amino acid, and nonsense mutations, which produce 1 of the 3 stop codons (UAA, UAG, or UGA) in the messenger RNA (mRNA), thereby terminating translation of the mRNA (shorter polypeptide chain). Conversely, if a stop codon is altered so that it encodes an amino acid, an abnormally elongated polypeptide can be produced. These alterations of amino acid sequences can have profound consequences. Because codons consist of groups of 3 base pairs, insertions or deletions can alter the downstream codons, resulting in a frameshift mutation. Other types of mutation can alter the regulation of transcription or translation. A promoter mutation can decrease the affinity of RNA polymerase for a promoter site, often resulting in reduced production of mRNA and, thus, decreased production of a protein. Mutations can also interfere with the splicing of introns, as mature mRNA is formed from the primary mRNA transcript. Splice-site mutations, those that occur at intron–exon boundaries, alter the splicing signal that is necessary for proper excision of an intron.Further Readinga.National Human Genome Research Institute; https://www.genome.govb.Lynn B, Jorde LB, Carey JC, Bamshad MJ. Genetic variation: Its origin and detection. IN: Medical genetics, 5th ed. New York, Elsevier, 2016:28–59. Aberrant drug metabolism commonly results from DNA variants when there is a narrow margin between doses required for efficacy and those causing toxicity, or when there is only a single main pathway for elimination of the drug (eg, CYP2D6, CYP3A4), or when there is allelic variation in drug transport molecules or in the transcriptional regulation of proteins such as enzymes, or transporters.2Evans W.E. Relling M.V. Pharmacogenomics: translating functional genomics into rational therapeutics.Science. 1999; 286: 487-491Crossref PubMed Scopus (2128) Google Scholar In contrast to somatically acquired genomic variants that are specific to cancer tissue, the gene variants of relevance in patients with IBS appear to be the result of germline variants. Polymorphisms of drug-metabolizing enzymes may modify functional groups of the enzyme, such as hydroxylation in phase 1 reactions, that make lipophilic molecules more water soluble. Cytochrome P450 (CYP450) enzymes (controlled by a family of 58 human CYP genes) account for about 75% or more of the phase 1 reactions. A second grouping or phase 2 enzyme reactions complete the processing to form excretable nontoxic substances. These result in the conjugation with endogenous substituents, and typical examples are transferases such as glucuronosyltransferases and catechol-o-methyl transferases. The pharmacogenomics of drug metabolism in IBS is mostly related to phase 1 metabolism, particularly CYP2D6 and 2C19. Some clinically relevant features of these drug metabolic variations are shown in Table 1. The geographical and racial distributions of altered activity variants are well illustrated by the documented prevalence of CYP2 enzymes in different regions (Figure 1).3Sistonen J. Fuselli S. JU Palo Chauhan N. Padh H. Sajantila A. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales.Pharmacogenet Genomics. 2009; 19: 170-179Crossref PubMed Scopus (146) Google ScholarTable 1Drugs Used in Treatment of IBS and Common Genetic Variations in Drug MetabolismCYPPrevalence of poor-metabolizing phenotypeExamples of drugs commonly used in IBSExample of drug metabolizedEffect of poor metabolizer polymorphism on that drug’s efficacy2D66.8% in Sweden; 1% in ChinaCentral neuromodulators: TCA: Amitriptyline, Nortriptyline, Desipramine; Tetracyclic: Mianserin; SSRI: Citalopram, Fluoxetine, Paroxetine, SNRI: Venlafaxine; Mixed: Mirtazapine, Analgesics: Opioids (codeine, oxycodone)Antinausea: Dolasetron, Ondansetron, Fluphenazine, Promethazine, Tropisetron, Antispasmodics (Ca2+ blockers): Diltiazem, Nicardipine, NifedipineNortriptylineCodeineEnhancedDecreased (as codeine is a prodrug that is converted to morphine to be effective)2C19∼3% in white individuals in the United States and Sweden; ∼16% in China, JapanPPIs (except rabeprazole [CYP3A4])H2 blockersCentral neuromodulators: clomipramine, ImipramineAnxiolytics: diazepamOmeprazoleRanitidineEnhancedEnhancedCYP, cytochrome P450; IBS, irritable bowel syndrome; PPI, proton pump inhibitor; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Open table in a new tab CYP, cytochrome P450; IBS, irritable bowel syndrome; PPI, proton pump inhibitor; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. The highest prevalence of poor metabolizers is in the CYP3A4/5 grouping, which was identified in 33% of a cohort (83% white, 17% black) studied in a New York City hospital.4Finkelstein J. Friedman C. Hripcsak G. Cabrera M. Pharmacogenetic polymorphism as an independent risk factor for frequent hospitalizations in older adults with polypharmacy: a pilot study.Pharmgenomics Pers Med. 2016; 9: 107-116PubMed Google Scholar However, the main classes of substrates of CYP3A4 are immunosuppressive, chemotherapeutic, antifungal, and antimicrobial agents. Thus, although CYP3A4/5 would be most relevant as a result of the high prevalence of poor metabolizers, there are few examples of classes of drugs used in patients with IBS that are impacted by poor metabolism by CYP3A4. The prokinetics, cisapride (5-HT4 receptor agonist) and erythromycin, which were never approved and are seldom used off-label for IBS, are metabolized by CYP3A4 and have been associated with torsades des pointes and cardiac arrhythmias, especially when used together with inhibitors of CYP3A4. Among medications that are 5-HT4 receptor agonists and are either approved in other countries (eg, prucalopride) or are in development (eg, velusetrag and naronapride) for the indications of functional constipation and IBS with constipation, only velusetrag undergoes metabolism by CYP3A4 (reviewed in Tack et al).5Tack J. Camilleri M. Chang L. et al.Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders.Aliment Pharmacol Ther. 2012; 35: 745-767Crossref PubMed Scopus (227) Google Scholar Figure 2 shows the nomenclature used to describe the cytochrome P450 enzymes including family, subfamily, isoenzyme, and allele. The outcomes of drug metabolism vary significantly between poor and ultrametabolizers. For CYP2D6, poor and ultrametabolizer statuses are estimated in 20–30 million or 15–20 million people, respectively, in the United States. The impact of polymorphisms on drug metabolism6Juran B.D. Egan L.J. Lazaridis K.N. The AmpliChip CYP450 test: principles, challenges, and future clinical utility in digestive disease.Clin Gastroenterol Hepatol. 2006; 4: 822-830Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 7Dalén P. Dahl M.L. Bernal Ruiz M.L. Nordin J. Bertilsson L. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes.Clin Pharmacol Ther. 1998; 63: 444-452Crossref PubMed Scopus (269) Google Scholar, 8Sheu B.S. Cheng H.C. Yeh Y.C. Chang W.L. CYP2C19 genotypes determine the efficacy of on-demand therapy of pantoprazole for reflux esophagitis as Los-Angeles grades C and D.J Gastroenterol Hepatol. 2012; 27: 104-109Crossref PubMed Scopus (6) Google Scholar, 9Kim M. Kong E. Genetic polymorphisms of cytochrome P450 2C19 in functional dyspeptic patients treated with cimetidine.Korean J Physiol Pharmacol. 2012; 16: 339-342Crossref PubMed Scopus (3) Google Scholar, 10Nassan M. Nicholson W.T. Elliott M.A. Rohrer Vitek C.R. Black J.L. Frye M.A. Pharmacokinetic pharmacogenetic prescribing guidelines for antidepressants: a template for psychiatric precision medicine.Mayo Clin Proc. 2016; 91: 897-907Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 11Ji Y. Skierka J.M. Blommel J.H. et al.Preemptive pharmacogenomic testing for precision medicine: a comprehensive analysis of five actionable pharmacogenomic genes using next-generation DNA sequencing and a customized CYP2D6 genotyping cascade.J Mol Diagn. 2016; 18: 438-445Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Bielinski S.J. Olson J.E. Pathak J. et al.Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol.Mayo Clin Proc. 2014; 89: 25-33Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar for active drugs is as follows:•Ultrarapid metabolizer: no drug response at ordinary dosage (nonresponders)•Extensive metabolizer: expected response to standard dose•Intermediate metabolizer: may experience a lesser degree of consequences of poor metabolizers•Poor metabolizer: too slow or no drug metabolism•too high drug levels at usual doses•high risk for adverse drug reactions (toxicity) It is important to note that the term “extensive” reflects the “normal” or expected response and does not imply excessive or ultrarapid metabolism. The impact of polymorphisms on drug metabolism for prodrugs is as follows:•Opposite effect to that of active drug•Ultrarapid metabolizers may suffer adverse events•Poor metabolizers may not respond A classic example of ultrarapid metabolism of a prodrug might be observed in patients treated with codeine, which has to be metabolized to morphine to have clinical efficacy, since codeine has 200-fold weaker affinity for the μ-opioid receptor than morphine.13Volpe D.A. McMahon Tobin G.A. et al.Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs.Regul Toxicol Pharmacol. 2011; 59: 385-390Crossref PubMed Scopus (261) Google Scholar CYP2D6 ultrarapid metabolizers, who have more than 2 functional copies of the CYP2D6 gene, generate excess morphine and are at risk for toxicity, including respiratory depression and death.14Crews K.R. Gaedigk A. Dunnenberger H.M. et al.Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.Clin Pharmacol Ther. 2014; 95: 376-382Crossref PubMed Scopus (473) Google Scholar In a study of 1013 US adult participants, CYP2D6 metabolizer phenotypes were ultrarapid for 8% and a poor metabolizer for 8% participants.12Bielinski S.J. Olson J.E. Pathak J. et al.Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol.Mayo Clin Proc. 2014; 89: 25-33Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Examples of specific alterations in drug pharmacokinetics and efficacy with treatment with tricyclic antidepressants,7Dalén P. Dahl M.L. Bernal Ruiz M.L. Nordin J. Bertilsson L. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes.Clin Pharmacol Ther. 1998; 63: 444-452Crossref PubMed Scopus (269) Google Scholar proton pump inhibitors,8Sheu B.S. Cheng H.C. Yeh Y.C. Chang W.L. CYP2C19 genotypes determine the efficacy of on-demand therapy of pantoprazole for reflux esophagitis as Los-Angeles grades C and D.J Gastroenterol Hepatol. 2012; 27: 104-109Crossref PubMed Scopus (6) Google Scholar and histamine H2 blockers9Kim M. Kong E. Genetic polymorphisms of cytochrome P450 2C19 in functional dyspeptic patients treated with cimetidine.Korean J Physiol Pharmacol. 2012; 16: 339-342Crossref PubMed Scopus (3) Google Scholar are provided in Table 1. The enzyme activity for CYP2D6 and CYP2C19 can be predicted by the identification of specific alleles (in the presence or absence of gene duplication)10Nassan M. Nicholson W.T. Elliott M.A. Rohrer Vitek C.R. Black J.L. Frye M.A. Pharmacokinetic pharmacogenetic prescribing guidelines for antidepressants: a template for psychiatric precision medicine.Mayo Clin Proc. 2016; 91: 897-907Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar to designate the metabolizer phenotypes as ultrarapid, extensive, intermediate, or poor metabolizer. For example, with CYP2C19, allele *17 is associated with increased, allele *1 with normal, allele *9 with decreased, and alleles *2–11 (null alleles) with no enzyme activity. Ultrametabolizer status is associated with 2 *17 alleles, whereas 2 *1 alleles result in extensive metabolizer status, and the combination of *1 and *2 or 2 *9 alleles with intermediate metabolizer status and 2 null alleles (*2–11) with poor metabolizer status.10Nassan M. Nicholson W.T. Elliott M.A. Rohrer Vitek C.R. Black J.L. Frye M.A. Pharmacokinetic pharmacogenetic prescribing guidelines for antidepressants: a template for psychiatric precision medicine.Mayo Clin Proc. 2016; 91: 897-907Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar These different levels of metabolism impact the potential for efficacy. For example, efficacy is reduced in ultrarapid metabolizers with directly acting drugs, or in slow metabolizers of a drug that needs to be activated or undergo bioconversion for efficacy. A classic example in hepatology practice is that the antiviral drugs, adefovir dipivoxil and tenofovir disoproxil, undergo bioconversion by esterases and phosphodieasterases, increasing their lipophilicity and increasing their oral bioavailability from ∼10% to ∼40%.15Rautio J. Kumpulainen H. Heimbach T. et al.Prodrugs: design and clinical applications.Nat Rev Drug Discovery. 2008; 7: 255-270Crossref PubMed Scopus (1126) Google Scholar In addition, the potential for adverse effects is impacted by the degree of metabolism; a slow metabolizer of a directly acting drug may result in high tissue levels that may indeed be the cause of adverse effects. These issues are examined in Table 1. The coadministration of drugs may also alter drug levels, such as when a catalytic enzyme is induced by a coadministered drug. The potentially relevant drug interactions through changes in drug metabolism are illustrated in Table 2. It is often stated that the most cost-effective drug is the right drug given at the right dose to the right patient. In this respect, it can be