kinetics 3.31Drug Metabolism and Pharmacokinetics

Introduction to Drug Metabolism

• We are approaching the end of the semester. Final exam structure:

  • Weighted twice as heavily as previous exams.

  • 50% review of prior content, 50% new content.

Key Concepts in Drug Elimination

• Drug Elimination: Comprises drug metabolism and drug excretion.

  • Metabolism: Primarily occurs in the liver, making drugs more hydrophilic for easier excretion.

  • Excretion: Some drugs may be excreted unchanged, while others are fully metabolized.

Drug Definition and Free Drug Concept

• Free Drug: Not attached to a protein; essential for binding to receptors to elicit pharmacodynamic responses.

• Bioavailability: The degree to which a drug becomes available to the target tissue after administration.

Drug Metabolism Process

Phase I Metabolism

• Introduction of Functional Groups: Involves exposing or introducing functional groups to lipophilic drugs, making them more hydrophilic.

• Enzymes Involved: Mixed function oxidases, particularly cytochrome P450 (CYP) enzymes.

Phase II Metabolism

• Conjugation Reaction: Attaching polar groups (e.g., sulfate, glucuronide) to Phase I metabolites.

• These reactions increase water solubility and facilitate excretion.

Phase III Metabolism

• Transport Proteins: Involved in moving drugs across cell membranes (efflux and uptake transporters).

• Examples include ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters.

Factors Influencing Drug Metabolism

• Age: Metabolism often slows with age.

• Sex, Pregnancy, and Disease: May alter metabolic processes.

• Drug-Drug Interactions: Certain drugs can induce or inhibit metabolism affecting other drugs.

  • Example: Grapefruit juice can inhibit CYP3A4, influencing drug metabolism.

Enzyme Systems in Drug Metabolism

Cytochrome P450 Variability

• Many CYP isoenzymes exist, with some being highly variable among individuals.

• An understanding of pharmacogenetics and pharmacogenomics is crucial, focusing on how genetic makeup affects drug metabolism.

Clearance Concepts

• Total Clearance: Composed of renal clearance and non-renal (hepatic) clearance.

• Intrinsic Clearance: Measures the liver's capacity to remove drug regardless of blood flow.

• Extraction Ratio (ER): Indicates the fraction of drug removed by the liver (% of drug perfusing the organ that gets metabolized).

High vs. Low Intrinsic Clearance

• High Intrinsic Clearance: Non-restrictive clearance; protein binding is not a limiting factor.

• Low Intrinsic Clearance: Restrictive clearance; protein binding significantly affects drug removal.

First Pass Effect

• Refers to the initial metabolism of drugs in the liver after absorption from the gastrointestinal tract but before entering systemic circulation.

• Drugs administered intravenously skip the first-pass metabolism.

• Bioavailability: Affected by the first-pass effect; measured as the area under the concentration-time curve (AUC).

Enterohepatic Recycling

• Concept: Drugs or metabolites excreted into the bile can be reabsorbed in the intestines, potentially prolonging their action.

  • Larger molecular weight metabolites (e.g., >500 Dalton) tend to be excreted in bile.

Summary of Drug Metabolism

• Pathway: A drug is metabolized through phases I and II, which increase hydrophilicity and prepare it for excretion via various routes, primarily the urine and bile.

• Understanding metabolism is crucial for predicting drug action and efficacy in different individuals and clinical settings.

Introduction to Drug Metabolism

• We are approaching the end of the semester. Final exam structure:

  • Weighted twice as heavily as previous exams, requiring comprehensive preparation.

  • 50% review of prior content, ensuring a solid understanding of foundational knowledge, and 50% new content, introducing advanced concepts in drug metabolism.

Key Concepts in Drug Elimination

• Drug Elimination: This process encompasses both drug metabolism and drug excretion, critical components in pharmacology and toxicology.

  • Metabolism: Primarily occurs in the liver, where enzymes transform lipophilic drugs into more hydrophilic metabolites. This alteration facilitates easier excretion through the kidneys or bile.

  • Excretion: Some drugs may be excreted unchanged, while others undergo extensive metabolism prior to elimination. This variation in metabolism can significantly influence a drug's therapeutic effects and side effects.

Drug Definition and Free Drug Concept

• Free Drug: Refers to the fraction of the drug that is not bound to proteins in blood plasma; this unbound state is essential for the drug to interact with its target receptors and elicit pharmacodynamic responses, such as therapeutic effects or adverse reactions.

• Bioavailability: Defined as the degree and rate at which an administered drug is absorbed and becomes available at the site of action. Factors such as formulation, route of administration, and first-pass metabolism can influence bioavailability.

Drug Metabolism Process

Phase I Metabolism

• Introduction of Functional Groups: This phase involves the exposure or introduction of polar functional groups into lipophilic drugs, significantly increasing their hydrophilicity. Such changes enhance their solubility in aqueous environments, facilitating further metabolism and excretion.

• Enzymes Involved: Mixed function oxidases, particularly cytochrome P450 (CYP) enzymes, play a pivotal role in this phase. The variety and activity of these enzymes can differ between individuals, affecting the metabolism rate of various drugs.

Phase II Metabolism

• Conjugation Reaction: In this phase, polar groups (such as sulfate, glucuronide, or glutathione) are covalently bonded to the Phase I metabolites, further increasing their water solubility and assisting in their excretion. This phase is critical in detoxifying drugs and facilitating their elimination from the body.

Phase III Metabolism

• Transport Proteins: These proteins are responsible for the active transport of drugs and metabolites across cellular membranes, both facilitating efflux out of and uptake into cells. Important examples include ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters, which significantly influence drug distribution and excretion processes within the body.

Factors Influencing Drug Metabolism

• Age: Metabolism typically slows with advancing age due to decreased liver function and enzymatic activity, leading to altered drug clearance rates.

• Sex, Pregnancy, and Disease: These biological factors can lead to significant changes in metabolic enzyme activity, potentially requiring dosage adjustments for optimal therapeutic outcomes.

• Drug-Drug Interactions: Certain drugs can induce or inhibit metabolic enzymes, affecting the metabolism of co-administered drugs and impacting their efficacy and safety. An example is grapefruit juice, which inhibits CYP3A4, a common enzyme involved in the metabolism of many drugs.

Enzyme Systems in Drug Metabolism

Cytochrome P450 Variability

• Numerous CYP isoenzymes exist, with genetic variability in their expression and function influencing how individuals metabolize different drugs. Understanding pharmacogenetics can guide personalized medicine approaches, optimizing drug therapy based on individual genetic profiles.

Clearance Concepts

• Total Clearance: The overall clearance of a drug from the body is composed of renal clearance (excretion through the kidneys) and non-renal clearance (primarily hepatic clearance via metabolism).

• Intrinsic Clearance: This measure reflects the liver's capacity to eliminate a drug independently of blood flow or perfusion, indicating the efficiency of hepatic metabolism.

• Extraction Ratio (ER): Represents the fraction of drug removed by the liver during its first pass through the organ. A high ER indicates significant metabolic activity and clearance.

High vs. Low Intrinsic Clearance

• High Intrinsic Clearance: Indicates non-restrictive drug clearance where factors like protein binding are less limiting to drug elimination processes.

• Low Intrinsic Clearance: Suggests restrictive clearance conditions, where protein binding heavily influences the elimination rate of drugs from the body.

First Pass Effect

• This phenomenon describes the initial metabolism that occurs in the liver after oral administration of drugs and before they enter systemic circulation. This can lead to a significant reduction in bioavailability for certain drugs.

• Drugs given intravenously avoid first-pass metabolism, often resulting in higher bioavailability compared to oral counterparts.

• Bioavailability: The first-pass effect can dramatically affect bioavailability, which is quantified by the area under the concentration-time curve (AUC) in pharmacokinetic studies.

Enterohepatic Recycling

• Concept: Following biliary excretion, drugs or their metabolites can be reabsorbed from the intestines, potentially extending their duration of action in the systemic circulation.

• Typically, larger molecular weight metabolites (e.g., those >500 Dalton) are more likely to undergo enterohepatic recycling, affecting overall drug efficacy and dosing considerations.

Summary of Drug Metabolism

• Pathway: The metabolism of drugs typically follows a sequential interaction through phases I and II, enhancing hydrophilicity and preparing drugs for excretion via various routes, predominantly urine and bile.

• Insights into metabolism are vital for predicting a drug's action, efficacy, and safety across diverse individuals and clinical contexts, thereby facilitating tailored pharmacotherapy.

1. What is biotransformation and how does biological variation affect it?

   • Biotransformation refers to the chemical modifications made by an organism on a chemical compound; it is primarily responsible for drug metabolism. Biological variation relates to the differences in genetic makeup, age, gender, and overall health among individuals that can lead to differing rates and effectiveness of biotransformation.

2. What is the summary of hepatic metabolism?

   • Hepatic metabolism involves the conversion of lipophilic drugs into more hydrophilic metabolites, primarily in the liver. This process is crucial for drug elimination and can affect the drug's efficacy and safety due to variations in enzyme activity across individuals.

3. How is hepatic clearance of drugs determined?

   • Hepatic clearance of drugs is determined by intrinsic clearance (the liver's ability to eliminate a drug without blood flow limitations) and the extraction ratio, which indicates the fraction of drug removed from circulation by the liver during its first pass.

4. What are first pass effects, and how do they influence drug bioavailability?

   • First pass effects refer to the initial metabolism of drugs in the liver after oral administration before they enter the systemic circulation. This can significantly reduce the bioavailability of some drugs compared to those delivered intravenously, bypassing first-pass metabolism.

5. What is enzyme kinetics in the context of drug metabolism?

   • Enzyme kinetics refers to the study of the rates at which enzymatic reactions occur, including how drug metabolism is influenced by factors such as enzyme concentration, substrate concentration, and the presence of inhibitors or activators.

6. How do biliary excretion and enterohepatic recycling affect drug metabolism?

   • Biliary excretion involves the elimination of drugs or their metabolites into bile, which can then be reabsorbed in the intestines, a process known as enterohepatic recycling. This recycling can prolong the effect of certain drugs and metabolites in circulation.