WK 5 -4 Pharmacokinetics_Elimination

JCU Pharmacokinetics: Metabolism and Excretion

Presented by: Robi IslamInstitution: James Cook University, AustraliaCelebrating 50 years: 1970-2020Copyright NoticeThis material is reproduced in accordance with the Commonwealth of Australia Copyright Regulations 1969 under section 113P of the Copyright Act 1968.The content is protected under copyright, and further reproduction may require permission.

Learning Objectives

• Define drug metabolism and elimination.

• Understand the roles and functions of drug metabolizing enzymes and their impact on drug activity and elimination.

• Identify various outcomes of drug metabolism, including the clinical significance of active and inactive metabolites.

• Recognize the major organs (such as the liver, kidneys, lungs, gastrointestinal tract, and blood) involved in drug metabolism and their respective roles.

• Differentiate clearly between Phase I and Phase II metabolic reactions, including the types of reactions that occur.

• Explain the role of CYP450 enzymes, particularly in drug-drug interactions and variability among patients.

• Discuss mechanisms of drug excretion, reabsorption, and secretion, and their relevance in pharmacotherapy.

• Calculate creatinine clearance to assess renal function and understand its implications for drug dosing and efficacy.

Enzymes involved in Drug Metabolism

Definition: Enzymes are specialized proteins that catalyze the biotransformation of drugs, leading to chemical reactions that are essential for biological processes, such as detoxification and drug activation.Example: Hexokinase catalyzes the transformation of glucose and ATP into glucose-6-phosphate and ADP, representing how metabolism activates necessary substrates for cellular processes.

Functions of Drug Metabolism

• Energy Provision: Generates ATP through the breakdown of drugs and other compounds, which is vital for maintaining cellular energy balance.

• Nutrient Conversion: Converts dietary nutrients into essential chemicals, such as amino acids or fatty acids, to support cellular functions and survival.

• Biomolecule Dynamics: Involves the synthesis and degradation of biomolecules, thus maintaining homeostasis.

• Hydrophilicity Increase: Enhances the excretion of xenobiotics (foreign chemicals) by increasing their solubility, facilitating their elimination from the body.

Outcomes of Drug Metabolism

• Modifications in pharmacokinetic or pharmacodynamic properties of drugs, altering their efficacy, safety, and duration of action.

• Termination of drug activity through metabolism, and conversion of prodrugs into their active forms, demonstrating the significance of metabolic pathways in drug efficacy.

• Removal of foreign chemicals from the body, transforming them into excretable metabolites that are typically more polar and water-soluble, enhancing elimination.

• Potential formation of toxic metabolites, which necessitates understanding metabolic pathways to prevent adverse drug reactions.

Major Sites of Drug Metabolism

Primary Sites:

• Liver: The primary organ where drug metabolism occurs, housing most drug-metabolizing enzymes.

• Gastrointestinal tract: Drug metabolism occurs within enterocytes, affecting bioavailability of orally administered drugs.

• Kidneys: Involved in the metabolism and excretion of certain drugs and metabolites.

• Lungs: Participate in metabolic reactions, particularly with inhaled substances.

• Blood: Contains enzymes that may metabolize drugs in circulation.

Metabolic Reactions

Phase I Reactions:

• Functionalization: These reactions involve adding functional groups to the drug molecule, primarily through hydrolysis, reduction, and oxidation facilitated by Cytochrome P450 enzymes (CYP450).

Phase II Reactions:

• Conjugation: In these reactions, endogenous molecules (like glucuronic acid) are added to the drug or its metabolites to increase solubility and facilitate excretion. Common conjugation reactions include glucuronidation, sulfonation, acetylation, and methylation.

Patterns of Biotransformation

Various metabolic reactions can produce either active or inactive metabolites from parent drugs.Examples:

• Acetylsalicylic acid → Salicylic acid (Active metabolite, responsible for anti-inflammatory effects).

• Losartan → Losartan carboxylic acid (Inactive metabolite, illustrating the importance of metabolism in drug action).

Cytochrome P450 (CYP) Superfamily

• The major enzymes responsible for the oxidation and reduction of drugs, minimizing toxicity and facilitating clearance of potentially harmful substances.

• Located in the membrane of the smooth endoplasmic reticulum, with some CYP enzymes highly polymorphic in the population.

• Example: CYP2D6 is a critical enzyme metabolizing around 25% of prescribed medications, yet comprises only 6% of total CYP content, demonstrating its high clinical relevance and implications for personalized medicine.

Drug-Metabolizing Enzyme Specificity

• Each enzyme exhibits a high degree of structural specificity; thus, a specific drug may serve as a suitable substrate for only one enzyme or a select few.

• Environmental factors (e.g., diet, substance use) and genetics influence drug metabolism, leading to variable responses among individuals.

Enzyme Inhibition and Induction

• Inhibition: Competing drugs can reduce each other’s metabolism (e.g., omeprazole inhibits warfarin metabolism, leading to increased blood levels of warfarin and greater anticoagulant effect).

• Induction: One drug can enhance the metabolism of another, potentially decreasing its therapeutic effect (e.g., rifampin induces CYP3A4, leading to lowered plasma concentrations of co-administered drugs).

Excretion/Elimination

Key Routes:

• Kidney (mainly): The primary route for drug excretion, with urine serving as the main output for cleared substances.

• Gastrointestinal tract: Involves excretion via feces and bile, providing an alternative elimination pathway for certain metabolites.

• Other routes: Drugs may also be excreted in sweat, saliva, tears, and expired air, although these routes are less significant in overall elimination.

Renal Excretion of Drugs

Processes Involved:

• Glomerular filtration: Involves the filtration of unbound drugs from blood into the renal tubule.

• Tubular secretion: Active transport mechanisms that remove drugs from the blood into the tubular lumen.

• Tubular reabsorption: The process of reclaiming substances from the tubular fluid back into the bloodstream, encompassing both passive and active transport mechanisms.

Renal Excretion Formula:

Excretion rate = Glomerular filtration rate + Tubular secretion rate - Tubular reabsorption rate.

Measuring Kidney Function

Creatinine Clearance (CrCl):

• A crucial metric for assessing renal function and determining stages of kidney disease. It helps inform drug dosing and therapeutic decision-making.

• Formula: [ C_{r} = \frac{Creatinine \ excretion \ rate}{Creatinine \ plasma \ clearance} ]

• Modifiers: Age, general health status, and concurrent medications may affect renal function, necessitating careful monitoring in clinical practice.

Summary of Elimination

• Most drugs undergo metabolism in the liver before being excreted by the kidneys, with both processes essential for overall drug elimination. Understanding these mechanisms is critical for optimizing therapeutic outcomes and minimizing adverse effects during drug therapy.