Abstract
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.
Keywords
drug metabolism, drug transporters, pharmacogenetics, pharmacogenomics, systems pharmacology, cytochrome P450, phase I metabolism, phase II metabolism
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. 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 ).
| 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 |
| Cessation of active drug effect Conversion of prodrug to active form Enhance suitability for elimination Conversion to toxic form |
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 ).
| 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 cytosine-guanine. 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. 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. 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), allowing for the existence of a putative normal genotype. Polymorphisms are also mutations; however, they are much more common (>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. 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. 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, 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 come (see Fig. 4.3 ). |
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 organizing these chemical processes into two phases of drug metabolism ( Table 4.4 ).
| Broad Function | Specific Reactions | Typical Enzymes | |
|---|---|---|---|
| Phase I | Alteration of a functional group (addition, or removal) Alters biologic activity (decrease, or increase) | Oxidation | Oxidases Dehydrogenases |
| Reduction | Reductases CYP | ||
| Hydrolysis | Esterases Phosphatases Hydrolases Lipases | ||
| Phase II | Alters water solubility for excretion | Glucuronidation | UDP-glucuronyltransferase |
| Sulfonation | Sulfotransferase | ||
| Acetylation | N-Acetyltransferase | ||
| Glutathione conjugation | Glutathione S-transferase | ||
| Methylation | Methyltransferase |
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 ).
Phase I Enzymes
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. 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. 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.
| Cytochrome P450 |
|
| Homeostatic Roles of Cytochrome P450 |
|
| 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 | Ethanol Isoniazid | ||
| CYP3 | 3A4 | Midazolam Alprazolam Diazepam Temazepam Lidocaine Methadone Fentanyl Alfentanil Sufentanil Amiodarone Nifedipine Verapamil | Grapefruit juice Aprepitant Ranitidine Clarithromycin Erythromycin Ketoconazole Verapamil Diltiazem | Barbiturates Phenytoin Carbamazepine Rifampicin Dexamethasone St John’s wort |
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. 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 practice (see Figs. 4.4 and 4.5 ). CYPs are the primary metabolic enzyme for numerous drug groups commonly used in anesthesia, including volatile anesthetics, 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 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.
Flavin-Containing Monooxidases
Flavin-containing monooxidases (FMOs) are a second major family of enzymes important in oxidative drug metabolism. Long-overlooked 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.
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 CYPs ; 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.
| 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 |
FMOs are distinct from CYPs in that they have a narrow specificity but high catalytic activity ( Table 4.8 ). Whereas CYPs 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. Another characteristic of FMOs is that they are resistant to induction or inhibition, making them less prone to drug interactions and an attractive target for drug design.
| 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 |
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. In particular, FMO3 has been shown to work in tandem with CYP3A4, 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.
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.
| 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 | |
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. 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 Chapter 13 , Chapter 14 , Chapter 21 ).
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, 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 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. In the fetus and neonate, glucuronidation activity is nearly absent and does not reach adult levels until 2 to 6 months of age. 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.
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 acetylators ( Table 4.10 ). “Slow acetylators” carry at least one reduced-function 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 carcinogens ( Table 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 | Mild decrease in serum hydralazine levels, no recommendation for dose adjustment | |
| Slow | Two copies of the reduced function allele | >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 |
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 ).
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%. 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. 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 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.
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