Drug Metabolism


Article Author:
Stephen Susa


Article Editor:
Charles Preuss


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/3/2019 11:42:18 AM

Introduction

Most drugs undergo chemical alteration by various bodily systems as a way to create compounds that are more easily excreted from the body. These chemical alterations occur primarily in the liver and are known as biotransformations. Understanding these alterations in chemical activity is crucial in utilizing the optimal pharmacological intervention for any patient, and is thus of interest to any provider who routinely treats patients with medication.[1][2][3][4]

Function

Biotransformations occur by mechanisms categorized as either phase I or phase II modifications. Phase I modifications alter the chemical structure of the drug, usually by oxidation. Oxidation typically results in metabolites that still retain some of their pharmacological activity. For example, the common anxiolytic drug diazepam is transformed into desmethyldiazepam and then to oxazepam by phase I modification. Both of these metabolites produce similar physiological and psychological effects of diazepam itself. Phase II modifications involve reactions that couple the drug molecule with another molecule in a process called conjugation. Conjugation usually renders the compound pharmacologically inert and water-soluble, so that the compound can easily be excreted. Oxazepam, the active metabolite of diazepam, is conjugated with a molecule called glucuronide such that it becomes physiologically inactive and is excreted without further chemical modification.

A critical factor in drug metabolism is enzymatic catalysis of these phase I and phase II processes. The type and concentration of liver enzymes are crucial to the efficient metabolism of drugs. The most important enzymes for medical purposes are monoamine oxidase and cytochrome P450. These two enzymes are responsible for metabolizing dozens of biogenic and xenobiotic chemicals. Monoamine oxidase, as the name suggests, catalyzes processing of monoamines such as serotonin and dopamine. Monoamine oxidase inhibitors (MAOI) are used as antidepressants, as they increase concentrations of serotonin and dopamine. Cytochrome P450 catalyzes the metabolism of many psychoactive drugs, including amphetamines and opioids.

Issues of Concern

Drug metabolism can affect the plasma concentrations of drugs. There is a concern of drug-drug interactions. For example, if rifampin is taken concomitantly with imatinib, imatinib's plasma concentrations can be reduced because rifampin can induce CYP3A4 activity. Thus, imatinib's anticancer activity can be attenuated.

Clinical Significance

In any kind of pharmacological intervention, it is important to consider how and when a specific drug is eliminated from the body. Most of the time, drug clearance takes place according to first-order kinetics, in other words, the rate of clearance depends on the plasma concentration of the drug. That is, the rate of elimination is proportional to drug concentration. The rate of this form of clearance depends on the chemical in question, and is often represented by half-life. This is the amount of time it takes for 50% of the drug to be eliminated. For example, the half-life of cocaine is approximately one hour; thus, after four hours, only about 6.25% of the initial dose is present in the body.

However, the elimination of some drugs occurs at a constant rate that is independent of plasma levels. Ethanol is one example; it is eliminated at a constant rate of about 15 ml/hour regardless of the concentration in the bloodstream. This is called zero-order kinetics and occurs when enzyme binding sites are saturated at low concentrations. Kinetics are of interest in medicine because monitoring of drug concentration is often of clinical importance with many medications. An understanding of pharmacokinetics, specifically elimination, allows providers to alter therapies in a patient-specific fashion. The goal of therapy is to achieve a steady-state plasma concentration at which drug metabolism and elimination occur at equal rates.

Metabolism is a highly variable process that can be influenced by a number of factors. One major disruptor of drug metabolism is depot binding, meaning, the coupling of drug molecules with inactive sites in the body, such that the drug is not accessible for metabolism. This can affect the duration of action of pharmacological agents susceptible to depot binding. One notable example is tetrohydrocannabinol (THC), the main psychoactive component of marijuana. THC is highly lipid soluble, and depot binds in the adipose tissue of users. This drastically slows the metabolism of the drug, which is why metabolites of THC can be detected in urine weeks after the last use. [5][6]

Another factor in drug metabolism is enzyme induction. Enzymes are induced by repeated use of the same chemical. The body becomes accustomed to the constant presence of the drug in question and compensates by increasing the production of the enzyme necessary for the chemical’s metabolism. This is a contributor to pharmacological tolerance and is one reason why patients need ever-increasing doses of certain drugs to produce the same effect. Opioids are a prime example. Patients with long-term prescriptions for opioid analgesics will notice that their medication becomes less effective over time. Notably, induction will increase the metabolic rate for all drugs processed via the enzyme induced; for example, chronic amphetamine use will induce higher concentrations of the enzyme CYP2D6. This enzyme is also important in the metabolism of certain opioids, such as oxycodone; thus, a physician prescribing oxycodone to a patient using amphetamines would have to give the patient a higher dose to produce the desired effect.[7]

In contrast, some drugs have an inhibitory effect on enzymes, making the patient more sensitive to the drugs metabolized with those enzymes. A classic example is the inhibition of monoamine oxidase by certain antidepressant drugs. These compounds produce their psychotherapeutic effects by blocking the enzyme that breaks down ‘pleasure’ chemicals in the brain. However, this can cause problems when patients on an MAOI take drugs that cause abnormally high concentrations of these chemicals. A patient on an MAOI who uses cocaine, which elevates concentration of serotonin, dopamine, and norepinephrine, will experience a much more potent effect from the cocaine. This can lead to numerous physiological problems, including tachycardia, hypertension, and serotonin syndrome.[8]

Drugs which share elements of their metabolic pathways can also ‘compete’ for the same binding sites on enzymes, decreasing the efficiency of their metabolism. For instance, alcohol and certain sedatives are metabolized by the same member of the cytochrome P450 family. Only a limited number of enzymes exist to break these chemicals down. Thus, if a patient were administered pentobarbital whilst also metabolizing alcohol, the pentobarbital would not be completely metabolized because most of the necessary enzymes would be filled by alcohol molecules. This is one reason that alcohol and other sedative/hypnotic drugs can have a synergistic effect when co-administered.

Enhancing Healthcare Team Outcomes

Drug metabolism is a very important clinical concern for the healthcare team. Physicians, nurses and pharmacists need to work together to prevent clinically important drug interactions which could affect the health of the patient.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Drug Metabolism - Questions

Take a quiz of the questions on this article.

Take Quiz
After metabolism, drugs usually become which of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
The majority of drug metabolism occurs in which organ?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A certain investigational drug, with a half-life of 4 hours, is given at a dose of 800 mg intravenously. How much of the drug is left in the serum after 12 hours?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following liver cytochrome P450 enzymes are implicated in most drug-drug interactions?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is most involved in the first pass metabolism of orally administered medications?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is the major mechanism of drug metabolism that goes on in the gastrointestinal system?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is considered a phase 1 reaction in liver metabolism of drugs?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the term for a phase II reaction that usually yields a more polar and, in most instances, an inactive metabolite?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A drug with a half-life of 3 hours is given intravenously. The drug is not excreted, only metabolized. How long will it take for there to be less than 4 percent of the drug present?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is a cause for the change in drug concentrations seen in the elderly?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is not a phase I reaction in the metabolism of drugs?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What will occur if the distribution of a drug is slower than biotransformation and elimination?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which tissues frequently store drugs?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is generally true about the metabolite of a drug after most biotransformation reactions?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
When compared to the parent compound, metabolites usually have which one of the following features?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
The biological half-life is often prolonged in newborn infants taking a drug because of which one of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Duration and intensity of a drug's action are directly affected by metabolism. Several factors influence the rate at which medications are metabolized. Understanding these factors will aid in the safe administration of medicines. Of the factors listed below, which one affects the rate at which a drug is metabolized?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Drug metabolism generally results in which one of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is generally true of the metabolism of a drug after it is absorbed by the gastrointestinal tract?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient presents to the emergency department complaining of intense musculoskeletal pain. He lists his medications as fluoxetine for depression, eletriptan for migraine headaches, and dextroamphetamine for ADHD. The physician on call administers a typical dose of hydrocodone, but the patient claims that his pain was not relieved. What could be the cause of his failure to respond?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Drug Metabolism - References

References

Wilde M,Pichini S,Pacifici R,Tagliabracci A,Busardò FP,Auwärter V,Solimini R, Metabolic Pathways and Potencies of New Fentanyl Analogs. Frontiers in pharmacology. 2019;     [PubMed]
Rizzieri D,Paul B,Kang Y, Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma. Journal of cancer metastasis and treatment. 2019;     [PubMed]
Pascale A,Marchesi N,Govoni S,Coppola A,Gazzaruso C, The role of gut microbiota in obesity, diabetes mellitus, and effect of metformin: new insights into old diseases. Current opinion in pharmacology. 2019 Apr 20;     [PubMed]
Azzam AAH,McDonald J,Lambert DG, Hot topics in opioid pharmacology: mixed and biased opioids. British journal of anaesthesia. 2019 Apr 19;     [PubMed]
Colizzi M,Weltens N,McGuire P,Van Oudenhove L,Bhattacharyya S, Descriptive Psychopathology of the Acute Effects of Intravenous Delta-9-Tetrahydrocannabinol Administration in Humans. Brain sciences. 2019 Apr 25;     [PubMed]
Patilea-Vrana GI,Anoshchenko O,Unadkat JD, Hepatic Enzymes Relevant to the Disposition of (-)-∆{sup}9{/sup}-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, 11-OH-THC. Drug metabolism and disposition: the biological fate of chemicals. 2019 Mar;     [PubMed]
Baldo BA, Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Archives of toxicology. 2018 Aug;     [PubMed]
Kotlinska-Lemieszek A,Klepstad P,Haugen DF, Clinically Significant Drug-Drug Interactions Involving Medications Used for Symptom Control in Patients With Advanced Malignant Disease: A Systematic Review. Journal of pain and symptom management. 2019 May;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of PA-Hospital Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for PA-Hospital Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in PA-Hospital Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of PA-Hospital Medicine. When it is time for the PA-Hospital Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study PA-Hospital Medicine.