Enzyme Reactions in Drug Metabolism

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Questions and Answers

What is the primary mechanism by which Phase I reactions increase hydrophilicity?

Conjugation of functional groups

Oxidation of compounds (correct)

Addition of methyl groups

Reduction of metabolites

What is a consequence of Phase II metabolism?

Increased metabolic activation

Facilitated excretion of compounds (correct)

Metabolism inhibition

Decreased polarity of compounds

Which of the following can inhibit drug metabolism?

Certain isoenzymes of CYP450 (correct)

Decreased enzyme synthesis

Increased drug solubility

Longer halflife of drugs

How long does the induction process typically take to reach its maximum effect?

4 to 14 days Signup and view all the answers

Which route of administration is primarily affected by First Pass Metabolism?

Oral Signup and view all the answers

What effect can metabolic induction have on a drug's action?

Lowered intensity or duration of action Signup and view all the answers

What role does grapefruit juice play in drug metabolism?

Inhibits metabolism by interacting with CYP450 Signup and view all the answers

What are the two main types of Phase I reactions?

Oxidation and reduction Signup and view all the answers

What primarily determines the efficiency of drug passage through cell membranes?

Plasma protein binding Signup and view all the answers

Which factor is NOT mentioned as influencing the rate of drug distribution?

Drug solubility Signup and view all the answers

How does high plasma protein binding affect drug availability?

Acts as a reservoir for slow release Signup and view all the answers

In which type of tissue is drug distribution expected to be the most challenging?

Muscle tissue Signup and view all the answers

What effect does saturable binding sites have on drug interaction?

It can lead to displacement of the drug Signup and view all the answers

Which of the following organs is least likely to have high drug concentration after administration?

Adipose tissue Signup and view all the answers

What characterizes low plasma protein binding drugs?

They are available for rapid metabolism and excretion Signup and view all the answers

Which two factors primarily impact the distribution of drugs to various organs?

Regional blood flow and cardiac output Signup and view all the answers

What is a characteristic of liposoluble drug distribution?

Better access to the brain and heart. Signup and view all the answers

How does hydrosoluble drug distribution primarily affect drug access in the body?

Restricts entry to the central nervous system (CNS). Signup and view all the answers

What role does the blood-brain barrier (BBB) play in drug distribution?

Restricts the diffusion of hydrophilic drugs into the CNS. Signup and view all the answers

Which condition can increase the volume of distribution (VD) of a drug?

Renal failure. Signup and view all the answers

What effect does liver failure have on drug distribution?

Can cause fluid retention and increased VD. Signup and view all the answers

Which factor primarily hinders hydrosoluble drugs from entering the central nervous system?

Lack of passive transport mechanisms. Signup and view all the answers

What mechanism is primarily involved in the transport of liposoluble drugs into the CNS?

Passive diffusion. Signup and view all the answers

Which of the following statements is true about drug distribution in special areas like the eye or fetal circulation?

Drug distribution can vary significantly based on tissue perfusion. Signup and view all the answers

What is one of the main roles of cytochrome P450 monooxygenases in drug metabolism?

To convert nontoxic molecules into toxic ones or inactive drugs into active ones. Signup and view all the answers

Which phase of drug metabolism is primarily responsible for conjugation reactions?

Phase II reactions. Signup and view all the answers

Which of the following conjugation reactions occurs primarily in the liver and produces water-soluble metabolites known as glucuronides?

Glucuronidation. Signup and view all the answers

What is the product of a hydrolysis reaction involving an ester and water?

An acid and an alcohol. Signup and view all the answers

Which group is commonly involved in phase II drug metabolism reactions for conjugation?

Hydroxyl (-OH) groups. Signup and view all the answers

What does acetylation in drug metabolism typically involve?

The conjugation of compounds with acetyl-CoA. Signup and view all the answers

Which metabolic process converts phase I metabolites into highly polar conjugates for excretion?

Conjugation reactions. Signup and view all the answers

Which of the following describes the nature of phase I reactions in drug metabolism?

They are non-synthetic reactions that modify drug structure. Signup and view all the answers

What is the primary site for drug excretion in the body?

Kidneys Signup and view all the answers

Which process can limit the systemic circulation of orally administered drugs?

First pass effect Signup and view all the answers

Which parameter is NOT considered in excretion kinetics?

Half-life Signup and view all the answers

How does the pH of urine affect the re-absorption of drugs?

Basic drugs are more ionized and less re-absorbed in acidic urine. Signup and view all the answers

What is one of the ways drugs are eliminated from the body through means other than excretion?

Air expiration Signup and view all the answers

Which of the following is considered a route of excretion for drugs?

Sweat Signup and view all the answers

What factor heavily influences the passive diffusion of lipophilic drugs during kidney excretion?

Urine pH Signup and view all the answers

Which of the following describes the total kidney excretion formula?

Glomerular filtration + Active secretion - Tubular re-absorption Signup and view all the answers

Study Notes

Comparing Phase I & Phase II Enzyme Reactions

Phase I reactions are oxidation, reduction, and hydrolysis reactions.
Phase II reactions are conjugation reactions.
Phase 1 increases hydrophilicity slightly.
Phase 2 increases hydrophilicity significantly.
Phase I exposes a functional group for a new reaction.
Phase II adds a polar functional group.
Phase I can lead to metabolic activation.
Phase II facilitates excretion.

Metabolism Inhibition

A drug can inhibit the metabolism of another drug if it uses the same enzyme or metabolism cofactors.
This is rare since different drugs typically use different isoforms of the CYP (P-450).
Inhibition can lead to toxicity effects due to a lack of drug elimination.
Some foods, like grapefruit juice, can inhibit drug metabolism.
Grapefruit juice is metabolized by an isoform of CYP450, thus preventing metabolism of the drug, leading to prolonged pharmacological effect.

Metabolism Induction

A drug can induce the metabolism of another drug by increasing the synthesis of metabolic enzymes.
Inductor drugs are highly selective for certain isoenzymes of the CYP (P-450).
Induction takes 4-14 days to reach maximum effect and lasts for 1-3 weeks.

Metabolism Induction Results

Metabolism induction can lead to lower or higher intensity and duration of drug effect.
Tolerance occurs when the drug itself induces its own metabolism.

First Pass Metabolism (PRE-systemic)

First Pass metabolism is the metabolism of a drug during its passage from the absorption site to systemic circulation.
Oral administration exposes drugs to metabolism in the intestine wall and liver.
Transdermal administration exposes drugs to metabolism in the skin (low relevance).
All routes expose drugs to metabolism in the lungs (low relevance).

Distribution

Distribution is the passage of a drug from the blood to different tissues and organs.
Important to consider when treating diseases located in specific areas, such as the CNS, and during pregnancy and lactation.

Factors Influencing Drug Distribution

Plasma protein binding: Many drugs have an affinity for plasma proteins, the most important of which is albumin.
- The less bound a drug is, the more efficiently it can cross cell membranes.
- Unbound drug fraction is available for pharmacological effects, metabolism, and excretion.
- Bound drug is not available.
- Plasma protein binding can influence the drug's biological half-life.
Regional blood flow: The rate of distribution to organs after absorption depends on the amount of cardiac output the organs receive.
- High vascularization (e.g. heart, kidney, liver) leads to faster drug distribution.
- Low vascularization (e.g. skin, adipose tissue, bone, skeletal muscle, brain) leads to slower drug distribution.
Liposolubility: Determines how quickly a drug is absorbed, crosses membranes, and settles in tissues
- Liposoluble drugs distribute well in highly irrigated organs (brain, heart, liver, kidneys) and more slowly to muscle, fat, and poorly irrigated tissues.
- Hydrosoluble drugs don't distribute well and struggle to access the CNS.
Distribution in Special Areas: CNS, eye, fetal circulation, and exocrine secretions (tears, saliva, milk, prostate fluid)
- The blood-brain barrier restricts the distribution hydrophilic drugs to the brain.

Volume of Distribution

Volume of distribution (VD) describes the extent of drug distribution between plasma and the rest of the body after oral or parenteral dosing.
VD can be increased by renal failure (fluid retention), liver failure (altered body fluid and plasma protein binding), and decreased in dehydration.
VD is typically involved in cytochrome P450 monooxygenase, NADPH, and oxygen activity.

Phase I Reactions

Oxidation: Most important, typically involves cytochrome P450 enzymes.
Reduction: Addition of hydrogen or removal of oxygen.
Hydrolysis: Molecule degradation by addition of a water molecule.

Phase II Reactions - Conjugation

Glucuronidation: Most important, mainly in the liver, catalyzed by UDP-glucuronyltransferase enzyme.
Acetylation: Involves acetyl-CoA conjugates.
Methylation: Addition of methyl groups forming conjugates.
Sulfation: Formation of sulfonates conjugates.
Glycine conjugation: Conjugation with glycine.
Glutathione conjugation: Involves glutathione disulfide and glutathione reductase.
Ribonucleosids and nucleotids synthesis: Conjugation of purine and pyrimidine antimetabolites.

First Pass Effect (Route of Orally Administered Drugs)

Drugs absorbed in the gastrointestinal tract pass through the portal venous system to the liver where they are exposed to first pass effect.
First pass effect can limit systemic circulation.
Once in systemic circulation, drugs interact with receptors in target tissues resulting in a pharmacological effect.

Excretion

Expulsion of a drug and its metabolites to the outside.
Essential process in all forms of life to eliminate non-useful materials from the organism.
Accumulation of foreign substances can negatively affect normal physiological functions.

Sites of Excretion

Kidney (most important, urine)
Biliary excretion (faeces)
Air expiration
Saliva and sweat
Breast milk
- Important during lactation as it can transfer drug metabolites to the baby.
- Low molecular weight and lipophilic drugs can easily pass through to the milk, but the amount that reaches the maternal milk is usually low.

Kidney Excretion

Responsible for water-soluble compounds.
Total kidney excretion = (Glomerular filtration + Active tubular secretion) - (Tubular re-absorption)
Glomerular filtration of unbound drug.
Tubular re-absorption of lipophilic and non-ionized drugs by passive diffusion.
- Affected by pH modifications.
- Basic drugs are more ionized and less re-absorbed in acidic urine.
- Acidic drugs are more ionized and less re-absorbed in alkaline urine.
Active secretion of free and protein-bound drug by transporters.

Excretion Kinetics

Important pharmacokinetic parameters to consider:
- Bioavailability (F)
- Volume of distribution (V)
- Clearance (CL)

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Description

Explore the critical differences between Phase I and Phase II enzyme reactions in drug metabolism. Understand how these phases affect hydrophilicity and the implications for drug interactions and metabolism inhibition, including the unique case of grapefruit juice. Test your knowledge on these essential biochemical processes.