2019- ch 4 hemmings drug meta and genetics.pdf

4 Drug Metabolism and Pharmacogenetics JUNE M. CHAN CHAPTER OUTLINE Evolutionary Perspective Pharmacogenetics, Pharmacogenomics and Variability in Drug Responses Pharmacokinetic Considerations Classification of Drug Metabolism Reactions Phase I Metabolism Phase II Metabolism Phase I Enzymes Cytochro...

4 Drug Metabolism and Pharmacogenetics JUNE M. CHAN CHAPTER OUTLINE Evolutionary Perspective Pharmacogenetics, Pharmacogenomics and Variability in Drug Responses Pharmacokinetic Considerations Classification of Drug Metabolism Reactions Phase I Metabolism Phase II Metabolism Phase I Enzymes Cytochrome P450 Flavin-Containing Monooxidases Amine Oxidases, Including Monoamine Oxidase Esterases, Including Butyrylcholinesterase (Pseudocholinesterase) Phase II Enzymes Sites of Drug Metabolism Liver Intestinal Mucosa Lung Blood Pharmacogenomics and Drugs Commonly Used in Anesthesia Neuromuscular Blockers Butyrylcholinesterase Deficiency Increased Butyrylcholinesterase Activity Opioids Pharmacokinetic Alterations Pharmacodynamic Alterations Intravenous Anesthetics Pharmacokinetic Alterations Pharmacodynamic Alterations Inhalational Anesthetics Pharmacokinetic Alterations Pharmacodynamic Alterations Serotonin Receptor Antagonists Emerging Developments Evolutionary Perspective The biotransformation of foreign substances is based on ancient evolutionary defense mechanisms. Hundreds of millions of years ago, animals evolved to terrestrial life and began ingesting new varieties of plant life with nutrient and toxic potential. These early organisms had to detoxify and eliminate any novel toxic compounds or perish. Enzyme systems that originally existed to maintain homeostatic functions gradually adapted to process exogenous toxins.1 The genetic heterogeneity of these metabolic enzymes exponentially increased as animals survived exposures to evermore diverse xenobiotics. The genetics of human metabolic enzymes today reflect both the foundational homeostatic role they played and the diversity of ancient evolutionary pathways. This has resulted in a wide range of interindividual variation in phenotypic responses to both xenobiotics and endogenous organic compounds. In this age of targeted drug development and precision medicine, the study of pharmacokinetics, pharmacodynamics, and pharmacogenomics has become increasingly interconnected to better understand the variation in drug effects (Tables 4.1 and 4.2). Pharmacogenetics, Pharmacogenomics, and Variability in Drug Responses Pharmacogenetics arguably began with Pythagoras, the sixth-century BCE mathematician who reported an association between the ingestion of fava beans and hemolytic anemia in certain individuals. The field grew rapidly in the 1950s, with the first reports of genetically determined responses to succinylcholine (scoline apnea) in 1956 and the birth of the term pharmacogenetics in 1959, coined by the German geneticist Friedrich Vogel. Subsequent investigations focused on identifying single-gene associations with variable drug responses: an early focus of study was the apparent bimodal half-life of isoniazid, an antituberculosis treatment, resulting from polymorphisms in N-acetyltransferase. With the sequencing of nearly the entirety of the human genome in 2003, deeper analysis of the relationships between multiple genes and drug responses became possible (Fig. 4.1). This has led to the evolution of pharmacogenomics, the study of the relationships between the entire genome, drug responses and human diseases (see Table 4.1). Although conditions with single-gene associations still exist (Fig. 4.2), it is increasingly evident that many unexplained variations in drug efficacy result from sources affecting multiple steps in the gene expression and biotransformation pathway (Tables 4.2 and 4.3; Fig. 4.3 and 4.4). Pharmacokinetic Considerations Classification of Drug Metabolism Reactions Pioneering studies in drug metabolism in the 1800s focused on identifying altered forms of ingested substances that were excreted in the urine. It was not until the 1950s that the enzyme systems responsible for these chemical reactions were identified. In 1959, R.T. Williams, a Welsh pharmacologist, first proposed 70 Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. CHAPTER 4 Drug Metabolism and Pharmacogenetics Abstract Keywords Biotransformation is an ancient and vital process that governs a drug’s pharmacokinetics and pharmacodynamics. The enzymes and transporters that control each step in the metabolic pathway are highly polymorphic. This can cause significant variability in drug effects between individuals, or when certain drugs are given in combination. Specific pharmacogenomics considerations apply to the majority of medications that are in clinical use today, including those particularly relevant to the practice of anesthesiology such as neuromuscular blockers, opioids, anesthetic agents and anti-emetics. Future developments in the fields of precision medicine, systems biology and bioinformatics can produce new models for characterizing complex genome-phenome associations, and improve understanding of interindividual variability in drug responses. drug metabolism drug transporters pharmacogenetics pharmacogenomics systems pharmacology cytochrome P450 phase I metabolism phase II metabolism Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. 70.e1 CHAPTER 4 TABLE Key Definitions 4.1 Biotransformation: Chemical alteration of a foreign molecule by the body Drug metabolism: The alteration of a drug by the body to allow for excretion Xenobiotics: A substance that is foreign to the body Pharmacokinetics: Study of the disposition of a drug within the body Pharmacodynamics: Study of the effects of the drug on the body Pharmacogenetics: Study of genetic (often single-gene) causes of variability in drug responses Pharmacogenomics: Genome-wide study of the determinants of variability in drug responses TABLE Outcomes of Drug Metabolism 4.2 Cessation of active drug effect Conversion of prodrug to active form Enhance suitability for elimination Conversion to toxic form Drug Metabolism and Pharmacogenetics 71 organizing these chemical processes into two phases of drug metabolism (Table 4.4). Phase I Metabolism Phase I metabolism broadly describes enzymatic reactions that alter biologic activity via the addition or alteration of a functional molecular group. For lipophilic compounds, this usually introduces a polar functional group that forms a substrate for subsequent metabolic handling. These alterations can inactivate or enhance the biologic effects of the parent drug, or they can introduce new activity such as in the case of prodrugs and certain carcinogenic compounds. Phase II Metabolism Phase II metabolism involves the addition of a cofactor to a compound. This typically results in a molecule that is highly water-soluble and amenable to excretion within the urinary or biliary tract. These enzymes usually require specific functional groups on their substrates for conjugation to occur: products of phase I metabolism are often good candidates for subsequent phase II reactions. However, it is not necessary for drugs to undergo both phase I and II metabolism, such as in the case of morphine, oxymorphone, and hydromorphone, which are readily glucuronidated by uridine diphosphate (UDP)-glucuronyltransferase (Fig. 4.5). Fig. 4.1 Schematic of gene, messenger ribonucleic acid (mRNA) and codon structures. Information within a gene must be transcribed into mRNA, which interacts with ribosomes to form proteins. During DNA transcription, regulatory regions within the DNA strand determine the genes to be transcribed and the amount of mRNA to produce. This initial pre-mRNA contains information from both exons and introns: once the introns are spliced out, the final mRNA is transported into the cytosol. Ribosomes on the endoplasmic reticulum then translate this mRNA into amino acids. Triplets of bases within mRNA, called codons, encode a single amino acid. Codons can also have regulatory functions in protein synthesis. There are 64 possible codon combinations and 20 amino acids; a single amino acid can have one or more corresponding codons. UTR, Untranslated region. Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. 72 SE C T I O N I Basic Principles of Pharmacology Phase I Enzymes A A T T C G C C G G T A A G C C G T A C T G 1 SNP 2 A A T T G C C G T T A A A G C C G T A C T G Fig. 4.2 Single-Nucleotide Polymorphisms (SNPs). An SNP is a form of genetic variation in which one base pair is substituted for another. In diploid organisms, this results in more than two genetic alleles for each locus, which, if expressed, can lead to the formation of a protein with altered function. Cytochrome P450 A group of major biotransformational enzymes in many organisms, including humans, is the cytochrome P450 (CYP) system. The CYPs are a superfamily of heme-containing proteins that contain several hundred distinct forms, located in cellular membranes in the endoplasmic reticulum and the inner mitochondrial membrane. Genetic studies of CYP DNA across a variety of organisms suggest that all currently known CYP originated from a common ancestor over two billion years ago, around the time that single-celled life forms evolved into complex, multi-organellar eukaryotes. 1 This long history has led to a vast array of genetic subfamilies within the CYP system. In humans, approximately 50 to 100 CYP enzymes are encoded by 57 functional genes and 58 pseudogenes spread across multiple autosomal chromosomes.8 These gene sequences are the basis for the classification of CYP families and subfamilies (Tables 4.5 and 4.6). This diversity is also seen in the vast array of CYP variants, which together with age, gender, and disease, is a major contributor to the variability in drug responses between individuals. CYPs are highly versatile enzymes capable of catalyzing numerous reactions, including reduction and hydrolytic reactions. This, combined with their affinity for many different substrates, makes CYPs the key biotransformational enzymes for a vast array of both xenobiotics and endogenous signaling molecules. More than 95% of oxidative metabolic processes in the body are performed by CYPs.9 In humans, a core cluster of enzymes in the CYP1, 2, and 3 families is responsible for the biotransformation of about 75% of all drugs currently used in clinical practice8 (see Figs. 4.4 and 4.5). CYPs are the primary metabolic enzyme for numerous drug groups commonly used in anesthesia, including volatile anesthetics, Epigenetic mechanisms Health endpoints are affected by these factors and processes: Development (in utero, childhood) Evironmental chemicals Drugs/pharmaceuticals Aging Diet Cancer Autoimmune disease Mental disorders Diabetes Chromosome Epigenetic factor Chromatin Methyl group DNA DNA methylation Methyl group (an epigenetic factor found in some dietary sources) can tag DNA and activate or repress genes. Gene Histone tail Histone tail DNA accessible, gene active Histone modification Histones are proteins around which DNA can wind for compaction and gene regulation. Histone DNA inaccessible, gene inactive The binding of epigenetic factors to histone “tails” alters the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be activated. Fig. 4.3 Epigenetic Modifications. Epigenomics is the study of inherited chromosomal changes that resulted in changes in phenotype without alteration in DNA sequences. The most common events are in form of DNA methylation and histone modification. Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. CHAPTER 4 Drug Metabolism and Pharmacogenetics TABLE A Brief Review of Genetics 4.3 Proteins are pivotal in sustaining life: enzymes, receptors, second-messenger systems, and cellular structural components are all proteins. The blueprint to individual protein structures is encoded by a specific sequence of DNA. DNA is composed of a deoxyribose backbone containing complementary base pairs, arranged in a double helical, ladder-like structure with 5′ to 3′ directionality. These base pairs are made up of adenine-thymine and cytosineguanine. The DNA strand is coiled into chromosomes, which are found in the cell nuclei. Within the DNA strand, there are sequences that code for proteins and those that do not. DNA sequences that encode proteins are termed genes. Noncoding sequences can have structural or regulatory roles in gene expression or no function at all. A gene is organized into regulatory regions bracketing the open reading frame, consisting of exons and introns with 5′ to 3′ directionality (see Fig. 4.1). The human genome has approximately 20,000 protein-coding genes, accounting for less than 2% of the human genome.2 Variations in pre-mRNA splicing, with selective inclusion of exons, result in many alternate mRNA sequences potentially coded from a single gene. This allows for a great many more proteins than the number of protein-coding genes currently identified. Mutation vs. Polymorphism vs. Variant The human genome has been highly preserved through the ages, with only 0.5% discordance between two unrelated individuals.3 In its simplest definition, a genetic mutation is any variation in the DNA base sequence within a gene. By convention, mutations are rare (1% of a population) and can be considered “normal variant” forms resulting from natural selection. The use of the term genetic variant is considered neutral. Variant forms of genes are called alleles, with the common allele termed wild-type and lesser forms termed minor alleles. Humans are diploid organisms (with two sets of paired chromosomes) and therefore carry two alleles of the same gene. Allelic variation in a single locus is responsible for the patterns described by simple Mendelian inheritance, but the addition of polygenic traits, polyallelic loci, and non-Mendelian patterns of inheritance add substantial complexity to the ultimate phenotype. The most common type of allelic variation is the single-nucleotide polymorphism (SNP), accounting for >70% of variations.4 This involves the variation in a single nucleotide base pair within the DNA strand (see Fig. 4.2). Sequence variants, including SNPs, are classified according to the affected domain (DNA, RNA, protein), their location in the sequence, and the alteration.5 There is currently no consensus nomenclature system established, which leads to potential confusion as the same variant can be described in multiple ways. SNPs can occur in coding and noncoding regions; coding region SNPs can be synonymous (not affecting the protein sequence) or nonsynonymous (affecting protein sequence). Nonsynonymous SNPs can be either missense or nonsense types; missense SNPs result in the substitution with an alternate amino acid, whereas nonsense SNPs usually result in a prematurely truncated, nonfunctional protein. As of 2017, more than 10 million SNPs have been identified,6 which corresponds to an average of one SNP for every 300 base pairs in the human genome. Genotype vs. Phenotype vs. Clinical Effect Most genetic variants do not result in any appreciable change in phenotype. The large proportion of noncoding sequences within the genome and the redundancy of translation systems reduce the possibility of clinically apparent sequelae. Conversely, heritable phenotypic differences can result between two populations without apparent alterations in their respective DNA sequences. This latter phenomenon is often the result of epigenetic modifications—that is, inherited variants in the chromosome rather than the DNA sequence itself. Epigenetic mutations result from events such as DNA methylation (which alters DNA transcription) and histone modification (which affects the packaging of DNA into chromatin) (see Fig. 4.3). Integrative “Omics”: Epigenomes, Transcriptomes, Proteomes, Metabolomes As genetic assaying and sequencing technology continues to advance, additional fields of study have opened to detail the steps along the path of genetic expression. Epigenomics is the study of heritable chromosomal alterations resulting in phenotypic changes, while transcriptomics investigates the total mRNA transcripts generated by a cell or organism under defined conditions. A proteome refers to the entire collection of proteins expressed by a particular cell or organism, which may greatly outnumber the genome; proteomics is the study of the proteins produced by the cell under different physiologic states, and the factors that determine the translation and post-translational modifications. Finally, metabolomics focuses on the dynamic array of metabolites formed by the enzymes coded within an organism’s genome. The integration of these fields into systems pharmacology and quantitative biology allows for large-scale modeling of complex physiologic or disease states, which has enormous potential to inform the study of drug interactions, and drug design, in the decades to come7 (see Fig. 4.3). Fig. 4.4 Systems Pharmacology and Variable Drug Responses. Systems pharmacology integrates knowledge from multiple fields of quantitative biology and bioinformatics to fully understand the factors contributing to interindividual variations in drug response. Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. 73 74 SE C T I O N I Basic Principles of Pharmacology TABLE The Phases of Drug Metabolism 4.4 Phase I Phase II Broad Function Specific Reactions Alteration of a functional group (addition, or removal) Alters biologic activity (decrease, or increase) Oxidation Alters water solubility for excretion Glucuronidation Sulfonation Acetylation Glutathione conjugation Methylation Reduction Hydrolysis TABLE Cytochrome P450: Essential Facts 4.5 Cytochrome P450 Typical Enzymes Oxidases Dehydrogenases Reductases CYP Esterases Phosphatases Hydrolases Lipases UDP-glucuronyltransferase Sulfotransferase N-Acetyltransferase Glutathione S-transferase Methyltransferase CYP, Cytochrome 450; UDP, uridine diphosphate First discovered in the 1960s. Named for their appearance; when reduced and bound to carbon monoxide has a pinkish hue, with peak ultraviolet light absorption at 450 nm. Humans have ~50–100 CYP enzymes across 18 families and 44 subfamilies; many of them have homeostatic or unknown functions. Isoform families are designated by letter, subfamilies by number. Homeostatic Roles of Cytochrome P450 1. Biosynthesis of lipophilic hormones and signaling molecules, including: Steroid hormone Prostaglandins, Thromboxane, Eicosanoids Bile and fatty acids Retinoids Vitamin D derivatives Porphyrins 2. Defensive detoxification against reactive intermediates and xenobiotic toxins 3. Potential unknown endogenous roles 13 CYP families with unknown “orphan” substrates CYP, Cytochrome 450. a result of competition at the substrate-binding active site. Other drugs can affect downstream oxygen-transferring functions of the CYP, which causes fully or partially irreversible enzyme inhibition. In contrast, CYP induction occurs in a time-dependent manner, usually as a result of a stimulus to increasing gene transcription and enzyme production, but the exact mechanism is unknown. This is believed to be an evolutionary defensive mechanism to toxin exposure by increasing the capacity to degrade the offending substance. In the case of toxins and certain drugs, this leads to a diminution of effect. For prodrugs and substances with active metabolites, however, enzyme induction can confer the risk of exaggerated drug effects and potential harm. Fig. 4.5 Contributions of Different Enzymes to Drug Metabolism. Cytochrome P450 enzymes are responsible for the vast majority of biotransformation reactions for drugs currently used today. This is closely followed by the uridyl-glucuronyltransferases and esterases. The flavincontaining oxygenases and monoamine oxidases (MAOs) make up a comparatively small percentage of overall drug metabolism, although limited research data suggest that their contribution is likely underestimated. CYP, Cytochrome P450; FMO, flavin-containing monooxidase; NAT, N-acetyltransferase; UGT, uridine phosphate-glucuronosyltransferase. (Data from Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, ed. Cytochrome P450, 4th ed., Vol. II. Cham, Switzerland: Springer International Publishing; 2015: 523–785.) intravenous hypnotics, opioid analgesics, and local anesthetic agents (see Table 4.6 and Fig. 4.6). Inducers and inhibitors influence the function of many CYPs. CYP inhibition is possible in almost all isoforms and can be reversible, irreversible, or partially irreversible. Conversely, only a select group of CYPs are inducible. Reversible inhibition is typically Flavin-Containing Monooxidases Flavin-containing monooxidases (FMOs) are a second major family of enzymes important in oxidative drug metabolism. Longoverlooked because of technologic constraints limiting their study, the role of FMOs in drug metabolism and homeostasis is increasingly being recognized, and is now shown to be responsible for approximately 2.5% of all metabolic reactions in the human body and about 6% of phase I metabolic reactions.10 FMOs contain a flavin adenine dinucleotide prosthetic group, which catalyzes oxidative reactions with reduced nicotinamide adenine dinucleotide phosphate as a cofactor. FMOs are found in all eukaryotes and appear to have followed an evolutionary development similar to CYPs11; however, in contrast to the vast genetic variety of CYPs, the six known human FMOs are encoded by six genes and six pseudogenes located on chromosome 1 (Table 4.7). Of the FMO subtypes, FMO3 has both the highest expression in the adult liver and the highest functional activity, and as a result is a major focus for pharmaceutical development. FMOs are distinct from CYPs in that they have a narrow specificity but high catalytic activity (Table 4.8). Whereas CYPs Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. CHAPTER 4 Drug Metabolism and Pharmacogenetics TABLE Cytochrome P450 Subfamilies, Substrates, Inhibitors, and Inducers 4.6 Family Subfamily Major Substrates Relevant to Anesthetic Practice Inhibitor Inducer CYP1 1A2 Local anesthetics Acetaminophen Cyclobenzaprine Ondansetron Haloperidol Olanzapine Warfarin Ciprofloxacin Fluvoxamine Cigarette smoke Omeprazole Phenytoin CYP2 2A6 Halothane Methoxyflurane Dexmedetomidine Nicotine 2B6 Alfentanil Methadone Propofol Sertraline Clopidogrel Rifampicin Carbamazepine 2C9 Ketamine Propofol Diclofenac Ibuprofen Parecoxib Celecoxib Amiodarone Aprepitant Carbamazepine Barbiturates Rifampicin 2C19 Diazepam Barbiturates Clopidogrel Warfarin Proton pump inhibitors Fluconazole Fluvoxamine Fluoxetine Omeprazole Barbiturates Rifampicin 2D6 Codeine Oxycodone Tramadol Methadone Duloxetine β-Blockers Metoclopramide Ondansetron Bupropion Duloxetine Fluoxetine Paroxetine Sertraline Quinidine Amiodarone Labetalol Celecoxib 2E1 Halothane Enflurane Sevoflurane Isoflurane Methoxyflurane Ethanol Caffeine Acetaminophen 3A4 Midazolam Alprazolam Diazepam Temazepam Lidocaine Methadone Fentanyl Alfentanil Sufentanil Amiodarone Nifedipine Verapamil CYP3 Ethanol Isoniazid Grapefruit juice Aprepitant Ranitidine Clarithromycin Erythromycin Ketoconazole Verapamil Diltiazem Barbiturates Phenytoin Carbamazepine Rifampicin Dexamethasone St John’s wort Data from Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, ed. Cytochrome P450, 4th ed., Vol. II. Cham, Switzerland: Springer International Publishing; 2015:523–785; and Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 2013;138:103–141. Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. 75 76 SE C T I O N I Basic Principles of Pharmacology TABLE Characteristics of Cytochrome P450 and 4.8 Flavin-Containing Monooxygenases Fig. 4.6 Contribution of Cytochrome P450 (CYP) Isoforms to Drug Metabolism. The CYP 3A family is responsible for the oxidative metabolism of almost half of the drugs currently in common use. The next CYP isoforms most involved in drug metabolism are 2C9, 2C19, and 2D6. While there are genetic variants associated with CYP 3A4 and 2C9, they are of insufficient frequency to contribute to any notable clinical effect. By contrast, polymorphisms in CYP 2D6 and 2C19 have significant clinical sequelae. (Data from Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, ed. Cytochrome P450, 4th ed, Vol. II. Cham, Switzerland: Springer International Publishing; 2015: 523-785.) TABLE Flavin-Containing Monooxygenases 4.7 Location Known Substrates FMO1 Fetal liver Adult kidney Chlorpromazine Imipramine FMO2 Adult lung Adult kidney Non-functional FMO3 Adult liver Adult lung Methamphetamine Ranitidine Diphenhydramine Olanzapine FMO4 Adult liver Adult kidney Insufficient data FMO5 Adult liver Adult intestine Insufficient data FMO, Flavin-containing monooxidase. Bold type indicates the dominant enzyme location. Data from Cruciani G, Valeri A, Goracci L, et al. Flavin monooxygenase metabolism: why medicinal chemists should matter. J Med Chem. 2014;57:6183–6196; Cashman JR, Zhang J. Human flavin-containing monooxygenases. Ann Rev Pharmacol Toxicol. 2006;46:65–100; and Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: structure/ function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther. 2005;106: 357–387. can bind readily to a broad variety of substrates, FMOs have a selective affinity for nucleophilic molecules (those containing a free pair of electrons, such as amines, sulfites, phoshites) but with approximately double the catalytic velocity of CYPs.11 Another characteristic of FMOs is that they are resistant to induction or Cytochrome P450 Flavin-Containing Monooxygenases Catalyzes ~75% of all metabolic reactions Catalyzes ~1%–2% of all metabolic reactions Can catalyze broad range of substrates Narrow substrate range Substrate affinity varies between isoforms High affinity for nucleophilic molecules (containing N, S, P, Se) Neutralize molecules via electrophilic reactions Neutralize molecules via nucleophilic addition Lower catalytic rate High catalytic rate Highly inducible and inhibited Resistant to inducers and inhibitors 50–100 CYP enzymes, encoded by 57 genes and 58 pseudogenes 6 FMO enzymes, encoded by 6 genes and 6 pseudogenes CYP, Cytochrome 450; FMO, flavin-containing monooxygenase. inhibition, making them less prone to drug interactions and an attractive target for drug design. To date, FMOs have been identified as key metabolic enzymes for antidepressants, antipsychotics, and antihistamines. Although the primary role of FMOs continues to be defined, they are known to play a complementary role to CYPs.12 In particular, FMO3 has been shown to work in tandem with CYP3A4,10 performing the same reactions on similar substrates but with a higher reaction capacity and velocity. It has been speculated that FMOs may play a role in mitigating CYP3A4 drug interactions and interindividual variations in activity.12 Amine Oxidases, Including Monoamine Oxidase Amine oxidases catalyze oxidative deamination reactions, producing ammonia and an aldehyde. These enzymes are critical to both homeostatic and xenobiotic metabolic pathways and are involved in the biotransformation of aminergic neurotransmitters (such as catecholamines, histamine, and serotonin) as well as toxins and carcinogens in foods and the environment. The monoamine oxidases (MAOs) are well studied and have been targets for drug therapy for more than 60 years. MAOs are flavin-containing mitochondrial enzymes distributed throughout the body. In humans, two isoenzymes of MAO have been identified, encoded by two genes located on the X chromosome: MAO-A and MAO-B. Each isoenzyme can be distinguished by certain substrate specificities and anatomic distribution (Table 4.9), although MAO-A has the distinction of being the sole catecholamine metabolic enzyme in sympathetic neurons. In neural and other selective tissues, MAOs catalyze the first step in the degradation of catecholamines into their aldehyde intermediaries, which is further processed by catechol-O-methyltransferase. The ubiquity of biogenic amines and their central role in neural and cardiovascular function make MAOs highly relevant to clinical anesthesia. The interactions between MAO inhibitors and drugs commonly used in anesthesia have been well described. Although genetic polymorphisms in MAO genes exist and are of great interest in the fields of neurology and psychiatry, to date none have been identified that specifically concern the handling of anesthetic agents. Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. CHAPTER 4 TABLE Monoamine Oxidases 4.9 MAO-A MAO-B Location CNS: sympathetic and catecholaminergic neurons Liver Pulmonary endothelium Gastrointestinal tract Placenta CNS: glia, serotoninergic neurons Platelets Specific Substrates Serotonin Melatonin Epinephrine Norepinephrine Dopamine Phenylethylamine Benzylamine Substrates for both MAO-A and MAO-B Dopamine Tyramine Tryptamine CNS, Central nervous system; MAO, monoamine oxidase. Further details on the agents that alter the function of MAO, and their effects on biotransformation of catecholamines, can be found in Chapter 12). Esterases, Including Butyrylcholinesterase (Pseudocholinesterase) Esterases catalyze hydrolysis of specific molecules containing the R1-CO-O-R2 ester group, as well as amides, hydrazides, and carbamates. In human physiology, esterases are distributed in the liver, erythrocytes, plasma, and the gastrointestinal tract. Proteases are specialized esterases and are involved in the activation of proenzymes such as those secreted by the pancreas. Cholinesterases are serine hydrolases with particular relevance to the practice of anesthesiology. Two types of cholinesterases have been identified, each encoded by a single gene: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE, also known as plasma cholinesterase or pseudocholinesterase). AChE has a key physiologic role in regulating cholinergic transmission and is a target for drug therapy in autonomic, central nervous system, and neuromuscular disorders (see Chapters 13, 14, and 21).13 BChE has been of great interest to anesthesiologists since the first description of variable responses to succinylcholine in the 1950s. Widely expressed in the liver, lung, brain, heart and plasma, it is also involved in the metabolism of mivacurium, cocaine, chloroprocaine, and tetracaine. Although the BChE gene shares 54% of the same amino acids as AChE,13 BChE appears to have a separate, albeit undefined, biologic role. Discussion of pseudocholinesterase deficiency continues later in this chapter (also see Chapter 21). Phase II Enzymes Transferases are the predominant enzyme type for phase II drug reactions. Functionally, transferases attach water-soluble sugars, amino acids, or salts to their substrates. This forms a metabolite that is more easily excreted by the kidneys or the biliary tract. Phase II reactions are classified according to the endogenous conjugate being catalyzed by its specific transferase enzyme (see Drug Metabolism and Pharmacogenetics 77 Table 4.4). In the adult, glucuronidation is the most common phase II process and is involved in the metabolism of approximately 40% to 70% of drugs in current clinical use.14 In the fetus and neonate, glucuronidation activity is nearly absent and does not reach adult levels until 2 to 6 months of age.15 This increases the risk of toxicity of compounds dependent on this pathway for metabolism, such as morphine and chloramphenicol. Sulfonation is well developed in the newborn and is the dominant conjugation pathway until UDP-glucuronyltransferase activity matures; this is demonstrated by the metabolism of acetaminophen, which is metabolized into sulfate conjugates in the first months of life, after which glucuronides become the major metabolite. Drug interactions involving the transferases are rare, but they are subject to genetic and environmental variations that are of clinical relevance. The UDP-glucuronyltransferases (UGTs) are involved in the metabolism of many drugs as well as endogenous substances, such as bilirubin, steroid hormones, bile acids, and fat-soluble vitamins. UGTs are membrane enzymes that are most concentrated in the liver and gastrointestinal tract but are also active in kidney, brain, pancreas, and placenta. Four UGT enzyme families have been identified in humans, with UGT1 and UGT2 the most heavily involved in drug metabolism. UGT 2B7 is the main isoform responsible for opioid glucuronidation, and although genetic polymorphisms have been identified for this enzyme, the large overlap in substrate specificity between the UGT enzymes has minimized any substantive phenotypic manifestation of these variants.14 Arylamine N-acetyltransferases (NATs) are cytosolic enzymes found in many tissues throughout the body and are associated with the metabolism of hydralazine, caffeine, procainamide, sulfonamides, and isoniazid. In humans, this enzyme family is encoded by the NAT1 and NAT2 genes, which are highly polymorphic. NAT2 gene polymorphisms have a higher degree of functional variation than NAT1 and multiple mutations result in three distinct phenotypes: fast (or wild-type), intermediate, and slow acetylators16 (Table 4.10). “Slow acetylators” carry at least one reducedfunction allele and are much more susceptible to drug toxicity. For example, slow acetylators who are administered hydralazine experience not only a greater degree of hypotension and tachycardia, but they are also at increased risk of hydralazine-induced lupus erythematosus. The current understanding is that in those with the slow-acetylator phenotype, the parent drug accumulates and is diverted to oxidative metabolic pathways. This produces reactive intermediaries, haptens, and carcinogens at levels that would be much lower in the intermediate- and fast-acetylator counterparts. This mechanism has been attributed to not only the development of drug-induced autoimmune disorders such as those seen with hydralazine and sulfonamides, but also the pathogenesis of bladder, breast, and colorectal cancer with chronic exposure to environmental carcinogens17 (Table 4.10). The methyltransferases include thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT). COMT is a magnesium-dependent enzyme that exists in soluble and membrane-bound forms found throughout the body. The soluble form is highly concentrated in the liver, while the membrane-bound form is predominantly found in the central nervous system and the chromaffin cells of the adrenal glands. It is one of the major metabolic pathways of catecholamines and related compounds such as levodopa and α-methyldopa. COMT is also a target for drug therapy: entacapone, a reversible inhibitor of COMT, is used in the treatment of Parkinson disease to increase the duration of action of levodopa (see Chapter 12). Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. 78 SE C T I O N I Basic Principles of Pharmacology TABLE Variant N-Acetyltransferase Phenotypes 4.10 Phenotype Genotype Approximate Frequency Clinical Effect Example Fast (wild-type) Two copies of the increased function allele 70% East Asians 70% Native Americans Normal activity of hydralazine Intermediate One copy each of an increased-function and a reduced-function allele Slow Two copies of the reduced function allele Mild decrease in serum hydralazine levels, no recommendation for dose adjustment >80% Scandinavians >80% Egyptians 70% South Asians 40%–70% Western Europeans 40%–70% African Americans Exaggerated drug effect of hydralazine Increased risk of hydralazine-induced lupus Data from McDonagh EM, Boukouvala S, Aklillu E, et al. PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenet Genomics. 2014;24:409–425; and Patin E, Barreiro LB, Sabeti PC, et al. Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes. Am J Hum Genet. 2006;78:423–436. TABLE Drug Transporters 4.11 Functionally, drug transporters mediate the uptake of drugs into cell, and the export of drugs and metabolites outside of cells. There are two major drug transporter superfamilies in humans: ABC (ATP-binding cassette) and SLC (solute carrier), each containing hundreds of transporter proteins whose function as yet is not fully understood (see Table 4.12). Phylogenetically, the ABC superfamily is among the oldest proteins associated with earth-bound life: member transporters are found across all current extant prokaryotic and eukaryotic life forms. They are especially important in oncologic pharmacogenomics as they determine the uptake and efficacy of chemotherapeutics. The P-glycoprotein (P-gp) efflux transporter is an ATP-dependent drug transport protein from the ABC transporter superfamily encoded by the ABCB1 gene, located in close proximity to the genes for the cytochrome P450 (CYP) 3A enzymes. It is located in the apical membranes of many epithelial cell types, including those of the gastrointestinal tract and brain and cerebrospinal fluid capillary endothelium. It is theorized that the wild-type P-gp works synergistically with CYP 3A enzymes within the gastrointestinal tract as a defense mechanism against xenobiotics and other toxic compounds, preventing their entry. They also likely contribute to maintaining the integrity of the blood-brain barrier. This efflux transporter has a broad specificity and extrudes a wide variety of substrates from cells, including opioids, β-blockers, calcium channel blockers, dexamethasone, ondansetron, digoxin and tricyclic antidepressants, as well as endogenous compounds such as conjugated bilirubin. The ABCB1 gene is highly polymorphic, with more than 100 single-nucleotide polymorphisms currently identified in humans.20 Patients with loss of function mutations in the ABCB1 gene can have increased clinical effects of P-gp substrates, and this finding is supported by several human studies. Similarly, many inducers and inhibitors of P-gp exist and can alter their function. For example, loperamide is a substrate for P-gp and is normally excluded from the enterocyte, which localizes its effect in the gastrointestinal tract. When coadministered with the P-gp inhibitors, the central effects of loperamide, such as sedation and respiratory depression, can occur. Organic anion-transporting peptides (OATPs), organic cation transporters (OCTs), and organic anion transporters (OATs) belong to the SLC transporter superfamily. These are genetically and structurally heterogeneous structures that are united by their function as uptake (and occasionally bidirectional) transporters.21 SLC transporters are located widely throughout the body in the liver, intestine, brain, heart, kidney and placenta. Drug-drug interactions are best described for orally administered medications, and those with a renal site of action or excretion such as diuretics and antihypertensives. One of the challenges in studying the effects of drug transporter variants in vivo is the overlapping substrate range of transporters and downstream metabolic enzymes. An example of this is the close genetic and functional relationship between P-glycoprotein and CYP 3A enzymes, and between several members of the SLC family and uridyl-glucoronyltransferase (UGT) 1A1.21 It is anticipated that with ongoing improvements in bioinformatics, these complex relationships will be unraveled and understood in the near future. ATP, Adenosine triphosphate. Variants of the COMT gene, located on chromosome 22, are typified by a complex spectrum of neuropsychological associations commensurate with the central role that catecholamines play in human behavior. The G472A polymorphism results in a methionine for valine substitution within the enzyme that diminishes its activity by approximately 25%.18 This increases the cortical neuronal levels of dopamine and has been linked to various disorders of executive functioning and cognition, including autism, attention deficit disorders, and schizophrenia.18,19 Anesthetic considerations for the G472A polymorphism are discussed further later in the chapter. Sites of Drug Metabolism Traditional thinking in pharmacokinetics and pharmacology summarize the factors influencing the disposition of a drug into four phases: absorption, distribution, metabolism, and excretion (ADME). This convenient but linear mnemonic overlooks the overlapping mechanisms that govern these processes. Drug transporters (Table 4.11) involved in absorption are essential for substrate delivery in metabolism and for drug excretion (Table 4.12). Biotransformational enzymes are widely present throughout the body and influence the absorption of certain drugs well before Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. CHAPTER 4 Drug Metabolism and Pharmacogenetics TABLE Selected Drug Transporter Systems 4.12 Family Transporter Substrates Inducer Inhibitor ABC P-glycoprotein (ABCB1 gene) Opioids, including Morphine Fentanyl Methadone Sufentanil Cardiovascular drugs, including Calcium channel blockers β-Blockers Statins Digoxin Antiemetics, including Ondansetron Dexamethasone St. John’s wort Trazodone Aspirin Rifampin Midazolam Amiodarone Dronedarone Carvedilol Lidocaine Verapamil Grapefruit juice SLC OATP Antihypertensives, including Aliskiren ACE inhibitors Angiotensin II receptor blockers Clarithromycin Erythromycin Grapefruit juice Pravastatin OAT Diuretics, including Furosemide Bumetamide Probenecid Benzylpenicillin OCT Antiarrhythmics, including Procainamide Dofetilide Cimetidine Trimethoprim Other Metformin Ranitidine ABC, Adenosine triphosphate-binding cassette; ACE, angiotensin-converting enzyme; OAT, organic anion transporter; OATP, organic anion-transporting peptide; SLC, solute carrier. Data from König J, Müller F, Fromm MF. Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol. Rev. 2013;65:944–966. they reach the circulation and biophase. Although the liver remains an important site for drug metabolism, many other locations are heavily involved in the metabolism of oral, inhaled, and intravenous drugs. Liver The liver is the largest organ in the body and the principal site of drug metabolism (see Chapter 31), and has a sinusoidal structure that creates a large blood-tissue interface. Almost all known metabolic enzymes are located in the smooth endoplasmic reticulum of the hepatocyte, including the major oxidases (see later). It receives 25% to 30% of total cardiac output and almost the entirety of portal vein flow, which carries substances absorbed through the gastrointestinal tract to the liver. This so-called first-pass exposure to enterally absorbed drugs functions as an important metabolic barrier between the gut and the systemic circulation. “First pass” may be a misnomer, as before this there is significant drug metabolism that occurs in the intestinal enterocyte. The total hepatic clearance of a specific compound is a function of the liver’s intrinsic capacity to metabolize and excrete that substance, the fraction of unbound drug, and hepatic blood flow (Table 4.13). The hepatic extraction ratio expresses hepatic clearance as a ratio of hepatic blood flow and is an indicator of the amount of drug removed during one pass through the liver. Active, energy-requiring drug transport is required for both entry into the hepatocyte (sometimes termed phase 0 metabolism) TABLE Hepatic Clearance and Extraction Ratio 4.13 [(Unbound drug × Metabolic capacity )] Hepatic =Q× , clearance [(Q + Unbound drug × Metabolic capacity )] where Q = hepatic blood flow. Drugs with high hepatic extraction ratio (> 0.7): Will have high first pass metabolism with oral administration Are highly sensitive to changes in liver blood flow: “flowlimited” clearance Less sensitive to alterations in drug binding or “intrinsic clearance” Examples: Morphine, lidocaine, verapamil, and nitroglycerin Drugs with low HER (T polymorphism decreases propofol metabolism and contributes to variations in propofol clearance when corrected for age, height, and weight.75,76 However, there appears to be little correlation between this and other genotypes with differences in clinical outcome.77,78 Similarly, the 766G>A SNP of UGT 1A9 decreases the glucuronidation of propofol but does not account for clinical variability in the effects of propofol.76,78 Pharmacodynamic Alterations The gamma-aminobutyric acid (GABA)A receptor is the molecular target for many intravenous and volatile anesthetics (see Chapters 10 and 11). In vitro studies of variant GABAA receptors with the epsilon subunit, encoded by the GABRE gene, show resistance to the effects of benzodiazepines, barbiturates, etomidate and propofol.79,80 Human studies, however, have so far been unable to show any association between the GABRE gene and variations in response to propofol anesthesia.77,78 Inhalational Anesthetics Pharmacokinetic Alterations The hepatic metabolism of halothane, sevoflurane, isoflurane, and desflurane occurs almost exclusively through CYP 2E1 oxidation.81 Although there are many known CYP 2E1 variants, to date no polymorphisms have been shown to cause clinically significant effects on the metabolism of volatile anesthetics. This can partly be attributed to the overall low contribution from liver metabolism to the disposition of sevoflurane, isoflurane, and desflurane (see Chapter 3). Halothane Hepatitis Reports of halothane hepatitis have become rare since the 1980s, but it remains relevant in those countries where halothane is still available for clinical use. The pharmacogenetic link between volatile anesthesia and acute, often fatal, liver injury remains elusive. Up to 20% of administered halothane is metabolized by hepatic CYP 2E1 and 2A6/3A4 via both oxidative and reductive pathways, respectively.81 Trifluoroacetyl chloride, an oxidative metabolite of halothane, is linked to the development of fulminant hepatocellular damage by covalently binding to hepatic proteins to form trifluoroacetylated neoantigens, which subsequently become a target for autoimmune attack (see Fig. 4.7). Risk factors include hypoxia and HLA tissue types, but there is little information on the pharmacogenetic features that predispose an individual to oxidative, rather than reductive, metabolism of halothane. To date, the single study investigating the CYP profiles of known survivors of halothane hepatitis have not demonstrated differences in activity between survivors and controls across a range of isoenzymes, including 2A6 and 3A4.82 An important omission, however, is the impact of CYP 2E1 activity in this survivor group. Pharmacodynamic Alterations Malignant Hyperthermia Malignant hyperthermia (MH) is an inherited, multifactorial channelopathy marked by uncontrolled release of calcium ions (Ca2+) from the sarcoplasmic reticulum of skeletal muscle in response to volatile anesthesia and succinylcholine (see Chapter 7). The main channels implicated in the pathogenesis of MH include the ryanodine receptor (encoded by the RYR1 gene), and the L-type calcium channel within the T-tubules containing the voltage-sensing CaV1.1 and beta1a subunits (encoded by the CACNA1S and CACNB1 genes, respectively). Many other defects in chromosomal loci not currently associated with genes are associated with MH.83 Given the complexity of Ca2+ homeostasis, it is likely these loci encode for other regulators of Ca2+ transport in skeletal muscle whose role in MH is still unknown. The pharmacogenetics of MH are complex and likely polygenetic. Approximately 50% to 85% of MH cases are linked to mutations in the RYR1 gene, although this varies depending on geographic population and study design.84 Inheritance is autosomal dominant, with unknown penetrance, but it is likely highly variable. The Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. CHAPTER 4 Drug Metabolism and Pharmacogenetics 85 Fig. 4.7 Pharmacogenetics of Halothane Hepatitis. Liver injury can occur as a result of oxidative and reductive metabolism of halothane, although it is the oxidative pathway that is most associated with more severe forms of hepatitis. Oxidative metabolism of halothane via CYP 2E1 results in trifluoroacetylated metabolites that covalently bind to liver proteins, resulting in neoantigens that stimulate an autoimmune response. While there are immunologic risk factors that predispose to halothane hepatitis, the role of CYP 2E1 isoforms and the production of trifluoroacetylated proteins has yet to be fully elucidated. prevalence of genetic variants in RYR1 predisposing to MH is estimated to be 1 : 2000,85 but the incidence of MH is much lower, between 1 and 1.3 per 100,000 anesthetics in the United States, and even lower in ambulatory surgical settings.86,87 Of the approximately 200 RYR1 mutations currently known,88 66 have been detected in known MH families in the United Kingdom.83 In approximately 10% to 20% of families, no RYR1 gene defect could be found. With regard to the CACNA1S gene, 6 of more than 50 known variants have been linked to MH,89 with approximately 1% of MH presentations attributed to defects in CACNA1S. What is increasingly clear from the genotype-phenotype discordance in both laboratory and human clinical studies is that there are additional modulators that influence the manifestation of MH. Post-translational modification of calcium channels by fatty acids90 and the interaction between these channels and other membrane proteins91,92 are implicated. When combined, the clinical manifestation of MH is likely a “threshold model” in which the presence of an RYR1 variant is but one of many other contributors that lead to symptoms. Melanocortin-1 Receptor Gene Variants Reduced-function variants of the melanocortin-1 receptor (MC1R) gene are associated with the red hair phenotype.93 The red hair trait occurs as a result of an overabundance of pheomelanin (red) pigment relative to eumelanin (dark brown)93 and is a convenient physical marker for reduced MC1R activity. In both knockout mice and humans, reduced-function MC1Rs are associated with increased volatile anesthetic and analgesic requirements.93–95 Whether these MC1R variants are directly responsible, or are markers for other determining characteristics common among red-haired individuals, is currently unknown. MTHFR Gene Variations Nitrous oxide irreversibly inhibits vitamin B12 (cobalamin), which leads downstream effects on enzymes that require vitamin B12 as a co-factor. Methionine synthase is one such enzyme, and is central to both the methylation of homocysteine to methionine, and to the conversion of 5-methyl-tetrahydrofolate (THF) to THF. Both metabolic reactions are crucial steps in methylation reactions critical to neurotransmitter, myelin sheath, and nucleic acid synthesis, which particularly affects central nervous system function and rapidly dividing cells such as those in bone marrow (Fig. 4.8). Furthermore, increased plasma homocysteine levels predispose to endothelial cell injury and vascular thrombosis. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate cycle that demethylates 5,10-methylene-THF to 5-methyl-THF, the substrate for methionine synthase. MTHFR deficiency occurs as a result of SNPs in the MTHFR gene located Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. 86 SE C T I O N I Basic Principles of Pharmacology Nitrous oxide Purine, pyrimidine synthesis MTHFR S-adenosylhomocysteine 5-Methyl-THF Homocysteine CH3 donation (DNA, proteins, phospholipids, catecholamines) Methionine synthase S-adenosylmethionine Methionine 5,10-methyleneTHF B12 Tetrahydrofolate (THF) Fig. 4.8 Nitrous Oxide and MTHFR Deficiency. Nitrous oxide inhibits vitamin B12, which is required by methionine synthase as a cofactor for catalyzing the conversion of 5-methyl-tetrahydrofolate to tetrahydrofolate (THF). Methylene tetrahydrofolate reductase (MTHFR) is an enzyme that converts 5,10-methylene-THF to 5-methyl-THF. In the presence of MTHFR deficiency, the administration of nitrous oxide can result in disorders of purine and pyrimidine synthesis, as well as other downstream reactions that depend on methyl donors from this metabolic cycle. on chromosome 1. The two common SNPs, 677C>T and 1298A>C, have a cumulative prevalence of approximately 5% to 10% in Western Europe, 20% to 25% in Southern Europe and East Asia, and up to 36% in Mexico.96,97 It has been postulated that nitrous oxide imposes a “second hit” to vulnerable patients with preexisting defects in folate or homocysteine-methionine metabolism pathways.98 Several case reports of repeated nitrous oxide anesthesia administered to patients with MTHFR gene mutations describe acute demyelination causing severe neurologic injury and megaloblastic anemia.98,99 Similar pathology is seen when nitrous oxide is administered to patients with severe vitamin B12 deficiency.100 Although an increase in plasma homocysteine levels is also seen in these patients, there is no correlation with increased risk of perioperative myocardial injury as a result of nitrous oxide anesthesia in these patients.101 Because of the potentially devastating effects of acute methionine synthase dysfunction, it has been suggested that nitrous oxide be avoided in patients who have a personal or family history of MTHFR gene mutation.102 Serotonin Receptor Antagonists Ondansetron and tropisetron are commonly used for the prevention and treatment of postoperative nausea and vomiting (see Chapter 34). Both are transformed into inactive metabolites: ondansetron by multiple CYPs, including 3A4, 1A2, and 2D6, and tropisetron exclusively by 2D6. Populations with the CYP 2D6 ultrarapid metabolizer phenotype can experience failure of antiemetic therapy when ondansetron and tropisetron are used. Within a group of 250 North American women undergoing general anesthesia treated with prophylactic ondansetron, those who were 2D6 ultrarapid metabolizers had a significantly higher incidence of postoperative nausea and vomiting (45%) compared with extensive metabolizers (15%).103 A similar failure of tropisetron for prevention of chemotherapy-induced nausea and vomiting occurs in 2D6 ultrarapid metabolizers.104 Interestingly, while poor metabolizers have increased serum drug levels compared with other phenotypes, there is no increase in side effects reported.103,104 Currently, expert opinion recommends avoidance of 5-HT3 antagonists primarily metabolized by CYP 2D6 in known ultrarapid metabolizers (ondansetron, tropisetron, dolasetron, palonosetron). Granisetron, an intermediateacting 5-HT3 antagonist, is metabolized by CYP 3A4 and 1A1 and is a suitable alternative in these patients. As yet, there are insufficient data to recommend specific changes in practice for poor metabolisers.105 Emerging Developments Precision medicine is an exponentially growing field that is increasingly bridging the gap between laboratory science and clinical application. The term, introduced into common usage in 2011, emphasizes the integration of population genomics with individual clinical and socio-environmental data to guide research and treatment of disease.106 An example of precision medicine in practice is the use of large-scale genetic databases and multiple patient biomarkers to individualize cancer chemotherapeutic regimens.107 Another example is point-of-care buccal swab testing for CYP 2C19 polymorphisms, used to predict non-responders to clopidogrel therapy in patients after percutaneous coronary intervention.108 It is increasingly recognized that for many drugs, the “one gene, one defect” paradigm is insufficient to fully explain the variability in drug responses between individuals. The use of massive data repositories for systems biology analysis is one approach that better characterizes these complex genome-phenome associations.109 The creation of robust, intricate biologic models is another approach; one example of this is the use of chimeric mice with “humanized” Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on March 08, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved. CHAPTER 4 livers.110 Xu and Peltz describe several methods that involve transplanting human liver cells into immunosuppressed transgenic mice, resulting in a biologically active liver that expresses mRNA encoding for human phase I and II enzymes, drug transporters, and other transcription factors.110 This exciting development expands horizons not only for more accurate prediction of in vivo drug handling, but also the promise of personalized, functional hepatic models through the engraftment of an individual’s hepatocytes in these chimeric mice. Drug Metabolism and Pharmacogenetics 87 In the near future, a fully integrated approach with contributions from the various “omic” bioinformatics branches can bring about virtual models of complex physiologic and disease states that can transform pharmaceutical development, clinical drug trials, and medication prescribing. In an era when guidelines and protocols are pervasive in clinical practice, precision medicine has the potential to be the personalized counterweight that brings about innovations in safety and cost-effectiveness in health care and research in the years to come. Key Points The transporters and enzymes involved with drug metabolism are closely related to ancient defense mechanisms against xenobiotics found across Archaea, bacteria, and eukaryotes. Pharmacogenetics is a term that refers to the study of genetic causes of variability in drug response; more recently, a genomewide approach has been adopted (pharmacogenomics) to more fully understand interindividual differences in drug effect. Genomic variants can alter the function of membrane transporters, metabolic enzymes, and target receptors to alter the disposition and effects of many commonly used anesthetic drugs. Genetic variants of membrane transporters are an important determinant of differential drug effect between individuals. While these variations alone can cause altered drug behavior, it is increasingly recognized that transporter variants may also alter the function of other enzymes and metabolites to contribute to changes in phenotype. Drug metabolism takes place predominantly in the liver, but begins with entry into the body via natural barriers of the gastrointestinal and respiratory tracts, and also occurs in many locations throughout the body. Drug metabolism processes can be classified into three phases: drug transport, phase I reactions, and phase II reactions. Phase I reactions alter biologic activity of drugs via alteration of a functional molecular group. Phase II reactions do so by conjugating a water-soluble adjunct to the drug. Important metabolic enzymes with variant phenotypes that have an impact on clinical care include CYP 2D6, 2C19, N-acetyltransferase, and butyrylcholinesterase. By overcoming current limitations in bioinformatics, laboratory technology, and study design, it is likely other similar associations will be found. The future of pharmacogenomics lies in systems pharmacology, using data from many “omic” fields to model and systems biology to model complex biologic states to guide drug development, test for efficacy, and minimize adverse side effects. Key References Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103–141. An exhaustive review of cytochrome P450 polymorphisms and their clinically important phenotypes. (Ref. 9). Hanley MJ, Cancalon P, Widmer WW, et al. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol. 2011;7:267–286. doi:10.1517/17425255.2011.553189. An in-depth examination of the “grapefruit juice effect” on oral drug bioavailability. (Ref. 28). Nebert DW, Dieter MZ. The evolution of drug metabolism. Pharmacology. 2000;61:124–135. A thought-provoking review of the origins of xenobiotic biotransformation, and how millions of years of evolution has resulted in our current knowledge of drug metabolism. (Ref. 1). Ritchie MD, Holzinger ER, Li R, et al. Methods of integrating data to uncover genotype-phenotype interactions. Nat Rev Genet. 2015;16:85–97. A review of how to advance the nascent field of systems pharmacology beyond our current understanding of drug metabolism and genomics. (Ref. 114). Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. 2012;379:1705–1711. A tantalizing example of pharmacogenomics and systems pharmacology put into practice today. (Ref. 113). Searle R, Hopkins PM. Pharmacogenomic variability and anaesthesia. Br J Anaesth. 2009;103:14–25. A comprehensive review of pharmacogenomics and its potential effects on commonly-used anesthesia drugs. (Ref. 88). Xu D, Peltz G. Can humanized mice predict drug “behavior” in humans? Annu Rev Pharmacol Toxicol. 2016;56:323–338. doi:10.1146/annurevpharmtox-010715-103644. A description of the techniques used to create chimeric mice with humanized livers, and case studies illustrating the applicability of this new methodology with several drugs of interest. (Ref. 115). References 1. Nebert DW, Dieter MZ. The evolution of drug metabolism. Pharmacology. 2000;61(3):124–135. 2. Ezkurdia I, Juan D, Rodriguez JM, et al. Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes. Hum Mol Genet. 2014;23(22):5866–5878. doi:10.1093/ hmg/ddu309. 3. Levy S, Sutton G, Ng PC, et al. The diploid genome sequence of an individual human. Rubin EM. PLoS Biol. 2007;5(10):e254. doi:10.1371/journal.pbio.0050254. 4. Frazer KA, Murray SS, Schork NJ, et al. 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