Agonist-to-Antagonist Spectrum of Action
According to Indian Health Service (IHS, 2020), an agonist is any drug that activates specific brain receptors, thus causing the full effect of the drug to take place (p. 1). A partial agonist is a drug that acts as an agonist but the degree of receptor activation is reduced. When a drug is classified as an antagonist, it means that the drug blocks the receptors so they are not able to bind to the agonist. In the realm of opioids, an example of an agonist is Heroin, the antagonist is Naloxone, and a partial agonist is Buprenorphine. To expand on this example, Heroin is an addictive agonistic substance. In the case of a Heroin overdose, Naloxone, an antagonist, can be used to reverse the binding and block receptors from binding with free-floating Heroin. Pharmacological treatment for Heroin addiction often includes the partial agonist, Buprenorphine. Buprenorphine allows partial binding to opioid receptors, thus reducing withdrawal symptoms and curving drug cravings (IHS, 2020, p. 2).
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Compare and Contrast: Ion Gated Channels and G-couple-proteins
Ion Gated Channels (IGCs) and G-protein-coupled receptors (GPCRs) are two classes of postsynaptic receptors. IGCs, also referred to as ligand-gated ion channels, have two domains. One domain functions to bind neurotransmitters (extracellular) and the other that forms the ion channel. GPCRs work via second messenger systems that are slower and rely on a variety of metabolic steps (Camprodon & Roffman, 2016, p. 47). GPCRs are also called metabotropic receptors. When the neurotransmitter binds to the metabotropic receptors, the G-proteins are activated. The G-proteins then separate from the receptor and directly interact with the ion channels or pair with effector proteins to control the ion channels via intracellular messengers (McEnery & Siegel, 2014, p. 552).
Epigenetics and Pharmacological Action
Epigenetics can be defined in many ways, but the basis is that gene function can be altered without changing the DNA and RNA code. This functional change in the gene can also be inherited (Camprodon & Roffman, 2016, p. 64). As a result, epigenetics can determine how a medication works and what illnesses an individual may develop. If a medication works on a specific gene, but that gene has an altered function, the drug’s efficacy may change. For example, individuals with altered dopamine formation and receptor binding may have an affinity towards drug addiction or a degree of natural tolerance (Saad et al., 2019, p. 1534). For non-addictive substances, this logic holds true as to why some medications work for one person, but not another individual.
It is essential to gather a thorough medical and family history before prescribing medications. Currently, the clinic I work in considers the patient’s familial medication history when prescribing medications, as well as genetic testing for patients where multiple psychotropics drugs have failed to treat their symptoms. As previously stated, some genes that affect medication efficacy may be inherited. In knowing what medications have worked for close relatives in the patient’s family, the patient may find success in using the same medication because of epigenetics.
Genetic Testing One of the reasons the genetic testing is performed is to assess if the patient has normal Methylenetetrahydrofolate reductase gene function and is able to convert Folate to L-Methyl-Folate (LMF). LMF is necessary for the production of serotonin, dopamine, and norepinephrine (Shelton, Manning, Barrentine, & Tipa, 2013, p. 2). If this is impaired, even with medication, the patient’s body is not appropriately producing enough of the LMF cofactor to produce the necessary neurotransmitters for a stable mood- hence drug-resistant depression. Medication prescribing is not “cookie-cutter.” Modern science gives prescribing providers greater insight into what is going on in the very foundation of their patient’s being, their DNA. Although some are skeptical of genetic testing for psychotropic medications, I have first-hand seen the benefits in my employer’s clinic by using this resource as a means of guided prescribing.
Camprodon, J. A., & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.),
Massachusetts General Hospital psychopharmacology and neurotherapeutics. Elsevier.
McEnery, M. W. & Siegel, R. E. (2014). Neurotransmitter Receptors. Encyclopedia of the Neurological Sciences, pp. 552-564. Retrieved from
Indian Health Service. (2020). Pharmacological Treatment. U.S. Department of Health and Human Services.
Retrieved from https://www.ihs.gov/opioids/recovery/pharmatreatment/
Saad, M.H., Rumschlag, M., Guerra, M.H.m Savonen, C. L., Jaster, A. M., Olson, P. D., Alazizi, A., Luca, F., Pique-Regi, R.,
Schmidt, C. J., & Bannon, M. J. (2019). Differentially expressed gene networks, biomarkers, long noncoding RNAs, and
shared responses with cocaine identified in the midbrains of human opioid abusers. Scientific Reports, 9, pp. 1534.
Retrieved from https://www.nature.com/articles/s41598-018-38209-8
Shelton, R. C., Sloan Manning, J., Barrentine, L. W., & Tipa, E. V. (2013). Assessing Effects of l-Methylfolate in Depression Management:
Results of a Real-World Patient Experience Trial. The primary care companion for CNS disorders, 15(4), pp. 1-11.
Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/?report=printable
Week 1: Introduction to Neuroscience
Modern psychopharmacology is largely the story of chemical neurotransmission. To understand the actions of drugs on the brain, to grasp the impact of diseases on the central nervous system, and to interpret the behavioral consequences of psychiatric medicines, one must be fluent in the language and principles of neurotransmission. NURS – 6630 Discussion: Foundational Neuroscience .
—Dr. Stephen M. Stahl in Stahl’s Essential Psychopharmacology
By using a combination of psychotherapy and medication therapy, psychiatric mental health nurse practitioners are positioned to provide a very unique type of care to clients with psychiatric disorders. To be successful in this role, you must have a strong theoretical foundation in pathophysiology, psychopharmacology, and neuroscience. This foundation will help you assess, diagnose, and treat clients as you relate presenting symptoms to theoretical neuronal functioning.
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This week, as you begin to study psychopharmacology, you explore foundational neuroscience. You examine the agonist-to-antagonist spectrum of action of psychopharmacologic agents, compare the actions of g couple proteins to ion gated channels, and consider the role of epigenetics in pharmacologic action.
Note: In previous courses, the term “patient” was used to describe the person receiving medical care. In traditional medicine and nursing, this term is used to describe the person you do something to, and it often refers to a passive recipient of care and services. As you move into the realm of psychiatric mental health, a transition will occur. You will work with individuals who are active participants in their care, and these individuals are generally referred to as “clients” as opposed to “patients.” It is important to note that the term “client” is also favored in other mental health disciplines, such as psychiatry, psychology, and social work. NURS – 6630 Discussion: Foundational Neuroscience .
Discussion: Foundational Neuroscience
As a psychiatric mental health nurse practitioner, it is essential for you to have a strong background in foundational neuroscience. In order to diagnose and treat clients, you must not only understand the pathophysiology of psychiatric disorders, but also how medications for these disorders impact the central nervous system. These concepts of foundational neuroscience can be challenging to understand. Therefore, this Discussion is designed to encourage you to think through these concepts, develop a rationale for your thinking, and deepen your understanding by interacting with your colleagues.
Analyze the agonist-to-antagonist spectrum of action of psychopharmacologic agents
Compare the actions of g couple proteins to ion gated channels
Analyze the role of epigenetics in pharmacologic action
Analyze the impact of foundational neuroscience on the prescription of medications
Note: To access this week’s required library resources, please click on the link to the Course Readings List, found in the Course Materials section of your Syllabus. NURS – 6630 Discussion: Foundational Neuroscience
Note: All Stahl resources can be accessed through the Walden Library using this link. This link will take you to a log-in page for the Walden Library. Once you log into the library, the Stahl website will appear.
Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY: Cambridge University Press *Preface, pp. ix–x
Note: To access the following chapters, click on the Essential Psychopharmacology, 4th ed tab on the Stahl Online website and select the appropriate chapter. Be sure to read all sections on the left navigation bar for each chapter.
Chapter 1, “Chemical Neurotransmission”
Chapter 2, “Transporters, Receptors, and Enzymes as Targets of Psychopharmacologic Drug Action”
Chapter 3, “Ion Channels as Targets of Psychopharmacologic Drug Action”
Document: Midterm Exam Study Guide (PDF). NURS – 6630 Discussion: Foundational Neuroscience
Document: Final Exam Study Guide (PDF)
Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents, including how partial and inverse agonist functionality may impact the efficacy of psychopharmacologic treatments.
Agonists are ligands that bind to receptors and alter or modify the state of the receptors in such a way it triggers a biological response, whereas antagonist are alpha or beta blocker ligands that refrain from or dampen a biological reaction but blocks the presenting receptors. A full agonist has the capability of producing maximal response of the target system. As the receptor stimulus invoked by an agonist maximizes its response capability as a full agonist in such system.
Partial agonists bind to and activate the presenting receptors; however, they do not have the ability to induce maximal intrinsic activity capable of producing full agonists even at full receptor occupancy and high concentration because of their low maximal efficacy when compared to the maximal efficacy of full agonists. When these partial agonists compete for the same receptors with full agonists they act as antagonists. Unless the partial agonists bind to the receptors in some sort of irreversible manner, it could be potentially be displaced from the receptor by a sufficiently high concentration of full agonist. In view of this, the efficacy of the full agonist is not affected, but its potency is reduced. Conversely, inverse agonists bind to receptors and reduce fraction of them in an active conformation. It could potentially decrease the available fraction of active receptors by binding to receptors in their inactive state preferentially, thus reducing the total possible pool of receptors in the system. In other words, an inverse agonist’s oppositional activity could be significantly reduced by competitive neutral antagonists that also bind the receptors but do nothing with them once they are attached (Camprodon and Roffman, 2016).
Compare and contrast the actions of g couple proteins and ion gated channels.
Neurotransmitter receptors such as acetylcholine that are ligand-gated ion channels have the tendency to mediate rapid postsynaptic responses while G protein – coupled neurotransmitter receptors such as serotonin and dopamine have the tendency to mediate slow postsynaptic responses. More so, a G protein-coupled receptor consist of a single polypeptide that is threaded over membrane, while ion channels comprise of pores that open and close upon ligand binding.
G protein coupled receptors interact with a variety of proteins for intracellular response, while ion channels regulate flow of ions. Finally, G protein involves GTP (Guanosine Triphosphate) whereas ion channels do not involve GTP.
Explain how the role of epigenetics may contribute to pharmacologic action.
The drug metabolism, as a biochemical process, requires modification of pharmaceutical substances through specialized enzymatic systems. Epigenetic regulation of drug-metabolizing enzyme genes has been shown to be a significant mechanism of changes in the expression of those drug-metabolizing enzymes. In other words, Drug absorption, distribution, metabolism, and excretion are critical processes to be considered when developing safe drugs. These identified processes are mediated by drug-metabolizing enzymes such as cytochrome P450 and transporters such as ATP-binding cassettes that are expressed in various tissues of the body such as the small intestine, liver, and kidney. These processes could potentially inhibit, limit, or enhance the systemic and target organ exposure to xenobiotics (Camprodon and Roffman, 2016). Drug-metabolizing enzymes such as cytochrome P450 isoforms are responsible for the metabolic elimination of drugs, and membrane transporters such as ATP-binding cassette transporters can affect drug absorption, distribution, and excretion processes. More so, the interplay of these drug-metabolizing enzymes and transporters could potentially determine the pharmacokinetic properties of a drug in areas of bioavailability, volume of distribution, and half-life, as well as understanding the regulation of drug-metabolizing enzymes and transporters are critical to the prediction of consequent pharmacological and toxicological effects.
Explain how this information may impact the way you prescribe medications to patients. Include a specific example of a situation or case with a patient in which the psychiatric mental health nurse practitioner must be aware of the medication’s action.
As a mental health nurse practitioner, it is extremely critical to understand that the pharmacokinetic properties such as the distribution, absorption, metabolism, and excretion processes of any given medication to be prescribed to a patient. More so, these processes identified above are significantly influenced by the route of administration as well as the functionality of the body organs. For instance, understanding the absorption, metabolic and distribution processes of enteral medications will make the prescribing practitioner be well informed that such medication is best absorbed in the stomach and should be best administered orally. Understanding the pharmacological and toxicological consequence or effect of a drug regarding dosage makes a huge difference in the favorability of the patient’s treatment outcome and could be a defining factor between life and death.
Camprodon, J. A., & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital psychopharmacology and neurotherapeutics (pp. 1–19). Elsevier.
Laureate Education (Producer). (2016i). Introduction to psychopharmacology [Video file]. Baltimore, MD: Author.
Note: The approximate length of this media piece is 3 minutes.
Laureate Education (Producer). (2009). Pathopharmacology: Disorders of the nervous system: Exploring the human brain [Video file]. Baltimore, MD: Author.
Note: The approximate length of this media piece is 15 minutes.
Dr. Myslinski reviews the structure and function of the human brain. Using human brains, he examines and illustrates the development of the brain and areas impacted by disorders associated with the brain.
Laureate Education (Producer). (2012). Introduction to advanced pharmacology [Video file]. Baltimore, MD: Author.
Note: The approximate length of this media piece is 8 minutes.
In this media presentation, Dr. Terry Buttaro, associate professor of practice at Simmons School of Nursing and Health Sciences, discusses the importance of pharmacology for the advanced practice nurse.
Agonists are drugs with both affinity (they bind to the target receptor) and intrinsic efficacy (they change receptor activity to produce a response (NCBI 2018). Antagonists have affinity but zero intrinsic efficacy and therefore they bind to the target receptor but do not produce a response. By occupying a fraction of the receptor population an antagonist reduces the probability of occupancy by an agonist. The presence of an antagonist will reduce receptor occupancy by an agonist with a corresponding reduction in response. By increasing the concentration of the agonist, the probability of receptor occupancy by the agonist increases, and thus the inhibitory/blocking effect of the antagonist can be surmounted (NCBI 2018). As intrinsic efficacy differs with drug structure, agonists can have different intrinsic efficacies and consequently be characterized as full or partial agonists. A full agonist typically produces the maximal response a system is capable of, whereas a partial agonist produces a submaximal response (NCBI 2018).
G proteins are a family of proteins that act as molecular switches inside cells and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. G-protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters, and environmental stimulants, and so have great potential as therapeutic targets for a broad spectrum of diseases (NCBI 2009). GPCRs are the largest family of membrane proteins and mediate most cellular responses to hormones and neurotransmitters, as well as being responsible for vision, olfaction, and taste (NCBI 2009). G protein-coupled receptors (GPCRs) are involved in the control of every aspect of our behavior and physiology (Hamm 2001). More than half of all drugs target GPCRs and either activate or inactivate them. GPCRs have a common body plan with seven transmembrane helices (Hamm 2001).
Ligand-gated ion channels (LGICs) are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane (Alexander et al,2017). Ligand-gated ion channels bind neurotransmitters and open in response to ligand binding. These channels control synaptic transmission between two neurons or between a neuron and a muscle. Ion channel function is modulated by interactions with other proteins (Alexander et al,2017).
Epigenetics is a mechanism of gene control that can promote or repress the expression of genes without altering the genetic coding of an organism (NCBI 2011). It represents a system by which the gene expression of an individual can be altered without altering their genome’s sequence. Unlike genetic changes, epigenetic changes are reversible and do not change the DNA sequence, but it can change how the body reads a DNA sequence (NCBI 2011). The disease may be caused by direct changes in epigenetic marks, such as DNA methylation found to affect imprinted gene regulation. Studies have found that exposure to risk factors such as toxins, stress, and unhealthy diets are associated with epigenetic changes which are associated with mental health problems. Epigenetic drugs belong to a category of drugs used for the treatment of specific cancers. These drugs fall into two groups DNA methylation inhibitors and histone deacetylase inhibitors (NCBI 2011). A nurse practitioner should be careful when prescribing psychiatric medication for a patient who is diagnosed with cancer or has a strong family history of cancer.
Alexander, S. P., Peters, J. A., Kelly, E., Marrion, N. V., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., & Davies, J. A. (2017). THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand-gated ion channels. British Journal of Pharmacology, 174 Suppl 1, S130–S159. https://doi.org/10.1111/bph.13879
Hamm, H. E. (2001). How activated receptors couple to G proteins. Proceedings of the National Academy of Sciences of the United States of America, 98(9), 4819–4821.
National center for biotechnology Information (NCBI 2018). Making sense of pharmacology: Inverse Agonism and functional selectivity. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165953/
National center for biotechnology Information (NCBI 2009). The structure and function of G-protein-coupled receptors. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967846/
National center for biotechnology Information (NCBI 2011). Epigenetics and Lifestyle. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752894/
To prepare for this Discussion:
Review this week’s Learning Resources.
Reflect on concepts of foundational neuroscience. NURS – 6630 Discussion: Foundational Neuroscience
Note: For this Discussion, you are required to complete your initial post before you will be able to view and respond to your colleagues’ postings. Begin by clicking on the “Post to Discussion Question” link and then select “Create Thread” to complete your initial post. Remember, once you click on Submit, you cannot delete or edit your own posts, and you cannot post anonymously. Please check your post carefully before clicking on Submit! NURS – 6630 Discussion: Foundational Neuroscience .
By Day 3
Post a response to each of the following:
Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents.
Compare and contrast the actions of g couple proteins and ion gated channels.
Explain the role of epigenetics in pharmacologic action.
Explain how this information may impact the way you prescribe medications to clients. Include a specific example of a situation or case with a client in which the psychiatric mental health nurse practitioner must be aware of the medication’s action. NURS – 6630 Discussion: Foundational Neuroscience
Read a selection of your colleagues’ responses.
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By Day 6
Respond to two colleagues in one of the following ways:
If your colleagues’ posts influenced your understanding of these concepts, be sure to share how and why. Include additional insights you gained. NURS – 6630 Discussion: Foundational Neuroscience
If you think your colleagues might have misunderstood these concepts, offer your alternative perspective and be sure to provide an explanation for them. Include resources to support your perspective.
Submission and Grading Information
To access your rubric:
Week 1 Discussion Rubric
Post by Day 3 and Respond by Day 6
To participate in this Discussion:
Week 1 Discussion
Now that you have:
Explored foundational neuroscience
Examined how medications impact the central nervous system
Next week, you will focus on how neuroscience can be applied to pediatric clients presenting with mood disorders. NURS – 6630 Discussion: Foundational Neuroscience
Week 2 Discussion-Main Post
This discussion will focus on the agonistic and antagonistic actions of psychotropic medications, ion channels, g coupled proteins, the role of epigenetics in pharmacologic action, and the efficiency in prescribing medication based on these factors. The understanding of these factors aids in determining the most effective course of treatment.
In receptor antagonism, a medication to promote reuptake reduction, such as the selective serotonin reuptake inhibitor (SSRI) sertraline, fills the receptor site, thus preventing the post-synaptic reuptake of the neurotransmitter serotonin (Camprodon and Roffman, 2016). Receptor agonism occurs when the medication has an affinity for specific receptor sites, as in an opioid’s affinity for mu receptors (Camprodon and Roffman, 2016). On the other hand, naltrexone is an opioid antagonist, which, when administered, dominates the mu receptor sites, preventing opioid agonist action. (Camprodon and Roffman, 2016). In the middle is the partial agonist. For example, buprenorphine is a partial mu-opioid receptor used in managing withdrawal from opiates as partial agonism provides enough activation of the opiate receptor to minimalize withdrawal symptoms and not promote a “high” (Camprodon and Roffman, 2016). Lastly, an inverse agonist is a molecule that produces an agonist’s opposite effect (Weir, 2020). An inverse agonist is only useful if the receptor site is active without an agonist present (Weir, 2020). Even if an antagonist is present, which competes for the same receptor site as an inverse agonist, without an agonist present, the antagonist is completely ineffectual (Weir, 2020).
Concerning coupled proteins, their role as a membrane receptor is intervening in the activity of neurotransmitters, various hormones and affecting heart contractility, sight, and inflammation (Calebiro and Grimes, 2020). In direct relation to g coupled proteins, ion channels are precisely affected by the action of g coupled proteins (Caleiro and Grimes, 2020). Once an agonist binds to the plasma membrane, a g coupled protein is recruited, followed by alteration in an ion channel (Calebiro and Grimes, 2020).
Another avenue in selecting a course of treatment involves epigenetics. For example, in anxiety disorders, research shows that dysfunctional gene expression resulting in the abnormal concentration of serotonin, GABA and norepinephrine, negatively impacts the body’s psychological and physiological state via increased and sustained cortisol levels (Peedicayil, 2020). To combat the effects of these dysfunctions, medication classes such as SSRIs inhibit the reuptake of serotonin, resulting in anxiolytic action (Peedicayil, 2020). In acute cases, immediate relief of symptoms is sought, which the benzodiazepine class is recommended (Peedicayil, 2020).
Fortunately, pharmacogenetic testing is available to reveal how the patient processes certain medications, thus ensuring the most efficient medication is selected for treatment. Pharmacogenetic testing shows if a patient is a normal, fast, or slow metabolizer of a specific medication based on the individual’s biological variant of drug-metabolizing enzymes and transporters (Yu et al., 2017).
Finally, as a psychiatric mental health nurse practitioner (PMHNP), these aspects of treatment must be considered to discover the best course of action. As a subjective opinion and prioritizing safety, if a PMHNP is contemplating starting a patient on a first-generation antipsychotic due to the patient’s failure to respond to safer and newer medications, pharmacogenetic testing is crucial. For example, a patient treated with haloperidol, which was personally witnessed, turned out to be a slow metabolizer of haloperidol after epigenetic testing results were released. These results explained why an initial 2.5 mg dose produced rapid extrapyramidal symptoms. With research showing that haloperidol most commonly produces extrapyramidal symptoms, extrapyramidal symptoms can develop rapidly, requiring emergency intervention (Boettger et al., 2015).
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Boettger, S., Jenewein, J., & Breitbart, W. (2015). Haloperidol, risperidone, olanzapine and aripiprazole in the management of delirium: A comparison of efficacy, safety, and side effects. Palliative & Supportive Care, 13(4), 1079–1085. https://doi.org/10.1017/S1478951514001059
Calebiro, D., & Grimes, J. (2020). G Protein-Coupled Receptor Pharmacology at the Single-Molecule Level. Annual Review of Pharmacology and Toxicology, 60, 73–87. https://doi.org/10.1146/annurev-pharmtox-010919-023348
Camprodon, J. A., & Roffman, J. L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation. T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital psychopharmacology and neurotherapeutics. Elsevier.
Peedicayil J. (2020). The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders. Neuropsychiatric Disease and Treatment, 16, 597–606. doi: https://doi.org/10.2147/NDT.S242040
Weir, C. J. (2020). Ion channels, receptors, agonists and antagonists. Anaesthesia & Intensive Care Medicine, 21(1), 62–68. https://doi.org/10.1016/j.mpaic.2019.10.022
Yu, A. M., Ingelman-Sundberg, M., Cherrington, N. J., Aleksunes, L. M., Ulrich M. Zanger, U. M., Xie, W., Jeong, H., Morgan, E. M., Turnbaugh, P. J., Klaassen, C. D., Aadra P. Bhatt, A. P., Redinbo, M. R., Hao, P., Waxman, D. J., Wang, L., & Zhong, X. B. (2017). Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta Pharmaceutica Sinica B, 7(2), 241–248. https://doi.org/10.1016/j.apsb.2016.12.006
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